U.S. patent application number 16/309980 was filed with the patent office on 2019-07-04 for 2-spiro-5- and 6-hydroxamic acid indanes as hdac inhibitors.
The applicant listed for this patent is FORMA Therapeutics, Inc.. Invention is credited to Pui Yee Ng, Mary-Margaret Zablocki, Xiaozhang Zheng.
Application Number | 20190201384 16/309980 |
Document ID | / |
Family ID | 59276843 |
Filed Date | 2019-07-04 |
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United States Patent
Application |
20190201384 |
Kind Code |
A1 |
Zheng; Xiaozhang ; et
al. |
July 4, 2019 |
2-SPIRO-5- AND 6-HYDROXAMIC ACID INDANES AS HDAC INHIBITORS
Abstract
The present invention is directed to inhibitors of histone
deacetylases (HDACs) such as HDAC6, and their use in the treatment
of diseases such as cell proliferative diseases (e.g., cancer),
neurological (e.g., neurodegenerative disease or neurodevelopmental
disease), inflammatory or autoimmune disease, infection, metabolic
disease, hematologic disease, or cardiovascular disease.
Inventors: |
Zheng; Xiaozhang;
(Lexington, MA) ; Ng; Pui Yee; (Waltham, MA)
; Zablocki; Mary-Margaret; (Revere, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
FORMA Therapeutics, Inc. |
Watertown |
MA |
US |
|
|
Family ID: |
59276843 |
Appl. No.: |
16/309980 |
Filed: |
June 16, 2017 |
PCT Filed: |
June 16, 2017 |
PCT NO: |
PCT/US2017/037970 |
371 Date: |
December 14, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62351399 |
Jun 17, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 209/54 20130101;
A61P 25/00 20180101; C07D 221/20 20130101; A61P 35/00 20180101;
A61P 29/00 20180101; A61P 25/14 20180101; A61P 25/28 20180101; A61K
31/407 20130101; C07D 401/04 20130101; C07D 401/06 20130101; A61K
31/438 20130101 |
International
Class: |
A61K 31/438 20060101
A61K031/438 |
Claims
1. A compound of the Formula I: ##STR00044## or a pharmaceutically
acceptable salt thereof, wherein: X.sup.1, X.sup.2, X.sup.3,
X.sup.4, X.sup.5, and X.sup.6 are each independently, at each
occurrence, --CR.sup.1R.sup.2-- or --C(O)--; Y.sup.1, Y.sup.2,
Y.sup.3 and Y.sup.4 are each independently, at each occurrence, N
or CR.sup.1, wherein --C(O)NHOH is attached at Y.sup.2 or Y.sup.3,
and Y.sup.2 or Y.sup.3 is a carbon atom when attached to
--C(O)NHOH; L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--; R is --H, --C.sub.1-C.sub.6alkyl,
--C.sub.2-C.sub.6alkenyl, --C.sub.4-C.sub.8cycloalkenyl,
--C.sub.2-C.sub.6alkynyl, --C.sub.3-C.sub.8cycloalkyl,
--C.sub.5-C.sub.12spirocycloalkyl, heterocyclyl, spiroheterocyclyl,
aryl, or heteroaryl containing 1-5 heteroatoms selected from the
group consisting of N, S, P, or O, wherein each alkyl, alkenyl,
cycloalkenyl, alkynyl, cycloalkyl, spirocycloalkyl, heterocyclyl,
spiroheterocyclyl, aryl, or heteroaryl is optionally substituted
with one or more --OH, halogen, oxo, --NO.sub.2, --CN, --R.sup.1,
--R.sup.2, --SR.sup.3, --OR.sup.3, --NHR.sup.3, --NR.sup.3R.sup.4,
--S(O).sub.2NR.sup.3R.sup.4, --S(O).sub.2R.sup.1, --C(O)R.sup.1,
--CO.sub.2R, --NR.sup.3S(O).sub.2R, --S(O)R.sup.1,
--S(O)NR.sup.3R.sup.4, --NR.sup.3S(O)R.sup.1, heterocyclyl, aryl,
or heteroaryl; R.sup.1 and R.sup.2 are independently, at each
occurrence, --H, --R.sup.3, --R.sup.4, --C.sub.1-C.sub.6alkyl,
--C.sub.2-C.sub.6alkenyl, --C.sub.4-C.sub.8cycloalkenyl,
--C.sub.2-C.sub.6alkynyl, --C.sub.3-C.sub.8cycloalkyl,
heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected
from the group consisting of N, S, P and O, --OH, halogen,
--NO.sub.2, --CN, --NHC.sub.1-C.sub.6alkyl,
--N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6alkyl).sub.2,
--N(C.sub.1-C.sub.6alkyl)S(O).sub.2R,
--S(O).sub.2(C.sub.1-C.sub.6alkyl),
--(C.sub.1-C.sub.6alkyl)S(O).sub.2R.sup.5,
--C(O)C.sub.1-C.sub.6alkyl, --CO.sub.2C.sub.1-C.sub.6alkyl,
--N(C.sub.1-C.sub.6alkyl)S(O).sub.2C.sub.1-C.sub.6alkyl, or
--(CHR.sup.5).sub.pNR.sup.3R.sup.4, wherein each alkyl, alkenyl,
cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl is optionally substituted with one or more --OH,
halogen, --NO.sub.2, oxo, --CN, --R.sup.5, --OR.sup.3, --NHR.sup.3,
--NR.sup.3R.sup.4, --S(O).sub.2N(R.sup.3).sub.2,
--S(O).sub.2R.sup.5, --C(O)R.sup.5, --CO.sub.2R.sup.5,
--NR.sup.3S(O).sub.2R.sup.5, --S(O)R.sup.5, --S(O)NR.sup.3R.sup.4,
--NR.sup.3S(O)R.sup.5, heterocyclyl, aryl, or heteroaryl; or
R.sup.1 and R.sup.2, when on the same atom, can combine with the
carbon atom to which they are attached to form a cycloalkyl,
heterocycle, spirocycloalkyl, spiroheterocycle, or
spirocycloalkenyl; or R.sup.1 and R.sup.2, when on adjacent or
non-adjacent atoms, can combine to form a heterocycle, cycloalkyl,
aryl, heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, or cycloalkenyl; R.sup.3 and R.sup.4
are independently, at each occurrence, --H, --C.sub.1-C.sub.6alkyl,
--C.sub.2-C.sub.6alkenyl, --C.sub.4-C.sub.8cycloalkenyl,
--C.sub.2-C.sub.6alkynyl, --C.sub.3-C.sub.8cycloalkyl,
heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected
from N, S, P, and O, --S(O).sub.2N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2(C.sub.1-C.sub.6alkyl),
--(C.sub.1-C.sub.6alkyl)S(O).sub.2R.sup.5,
--C(O)C.sub.1-C.sub.6alkyl, --CO.sub.2C.sub.1-C.sub.6alkyl, or
--(CHR.sup.5).sub.pN(C.sub.1-C.sub.6alkyl).sub.2, wherein each
alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl,
aryl, and heteroaryl is optionally substituted with one or more
substituents selected from --OH, halogen, --NO.sub.2, oxo, --CN,
--R.sup.5, --O(C.sub.1-C.sub.6)alkyl, --NH(C.sub.1-C.sub.6)alkyl,
--N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2NHC.sub.1-C.sub.6alkyl, --C(O)C.sub.1-C.sub.6alkyl,
--CO.sub.2C.sub.1-C.sub.6alkyl,
--N(C.sub.1-C.sub.6alkyl)S(O).sub.2C.sub.1-C.sub.6alkyl,
--S(O)R.sup.5, --S(O)N(C.sub.1-C.sub.6alkyl).sub.2,
--N(C.sub.1-C.sub.6alkyl)S(O)R.sup.5, heterocyclyl, aryl, or
heteroaryl; R.sup.5 is independently, at each occurrence, --H,
--C.sub.1-C.sub.6alkyl, --C.sub.2-C.sub.6alkenyl,
--C.sub.4-C.sub.8cycloalkenyl, --C.sub.2-C.sub.6alkynyl,
--C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from N, S, P and O, --OH,
halogen, --NO.sub.2, --CN, --NHC.sub.1-C.sub.6alkyl,
--N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-C.sub.6alkyl),
--S(O).sub.2N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2C.sub.1-C.sub.6alkyl, --C(O)C.sub.1-C.sub.6alkyl,
--CO.sub.2C.sub.1-C.sub.6alkyl,
--N(C.sub.1-C.sub.6alkyl)SO.sub.2C.sub.1-C.sub.6alkyl,
--S(O)(C.sub.1-C.sub.6alkyl), --S(O)N(C.sub.1-C.sub.6alkyl).sub.2,
--N(C.sub.1-C.sub.6alkyl)S(O)(C.sub.1-C.sub.6alkyl), or
--(CH.sub.2).sub.pN(C.sub.1-C.sub.6alkyl).sub.2; p is 0, 1, 2, 3,
4, 5, or 6; n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; and wherein the
sum m+n.ltoreq.4.
2-31. (canceled)
32. The compound of claim 1, wherein n is 0.
33. The compound of claim 32, wherein m is 1.
34. The compound of claim 32, wherein m is 2.
35. The compound of claim 1, wherein n is 1.
36. The compound of claim 35, wherein m is 1.
37. The compound of claim 1, wherein X.sup.1 is --CH.sub.2-- and
X.sup.2 is --CH.sub.2--.
38. The compound of claim 1, wherein X.sup.5 is --C(O)--.
39. The compound of claim 37, wherein Y.sup.1 and Y.sup.4 are each
CR.sup.1, wherein --C(O)NHOH is attached at Y.sup.2 or Y.sup.3, and
Y.sup.2 or Y.sup.3 is a carbon atom when attached to
--C(O)NHOH.
40. The compound of claim 39, wherein L is a bond,
--(CR.sup.1R.sup.2).sub.p--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
41. The compound of claim 40, wherein p is 0 or 1.
42. The compound of claim 41, wherein R is --H or an optionally
substituted group selected from --C.sub.1-C.sub.6alkyl, aryl, and
heteroaryl.
43. The compound of claim 42, wherein R is an optionally
substituted group selected from aryl or heteroaryl.
44. The compound of claim 1, wherein the compound is of the Formula
IA-1: ##STR00045##
45. The compound of claim 1, wherein the compound is of the Formula
IA-2: ##STR00046##
46. The compound of claim 1, wherein the compound is of the Formula
IA-3: ##STR00047##
47. The compound of claim 1, wherein the compound is of the Formula
IA-4, Formula IA-5, Formula IA-6, Formula IA-7, or Formula IA-8:
##STR00048##
48. The compound of claim 1, wherein the compound is of the Formula
IB-1, Formula IB-2, Formula IB-3, Formula IB-4, Formula IB-5,
Formula IB-6, Formula IB-7, or Formula IB-8: ##STR00049##
49. A compound of claim 1 selected from:
(R)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-1);
(S)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-2);
(R)--N-hydroxy-1'-isopropyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidi-
ne]-5-carboxamide (I-3);
(S)--N-hydroxy-1'-isopropyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidi-
ne]-5-carboxamide (I-4);
(R)-1'-ethyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-
-carboxamide (I-5);
(S)-1'-ethyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-
-carboxamide (I-6);
(R)--N-hydroxy-1'-isobutyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidin-
e]-5-carboxamide (I-7);
(S)--N-hydroxy-1'-isobutyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidin-
e]-5-carboxamide (I-8);
(R)--N-hydroxy-1'-(2-methylbenzyl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-py-
rrolidine]-5-carboxamide (I-9);
(S)--N-hydroxy-1'-(2-methylbenzyl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-py-
rrolidine]-5-carboxamide (I-10);
(R)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]--
5-carboxamide (I-11);
(S)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]--
5-carboxamide (I-12);
(R)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-13);
(S)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-14);
(R)-1'-(4-fluorophenyl)-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyr-
rolidine]-5-carboxamide (I-15);
(S)-1'-(4-fluorophenyl)-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyr-
rolidine]-5-carboxamide (I-16);
(R)--N-hydroxy-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-17);
(S)--N-hydroxy-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-18);
(R)--N-hydroxy-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-19);
(S)--N-hydroxy-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-20);
(R)--N-hydroxy-2'-oxo-1'-(pyridin-4-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-21);
(S)--N-hydroxy-2'-oxo-1'-(pyridin-4-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-22);
(R)--N-hydroxy-2'-oxo-1'-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3-
'-pyrrolidine]-5-carboxamide (I-23);
(R)--N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carb-
oxamide (I-24);
(S)--N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carb-
oxamide (I-25);
(R)-1'-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carbo-
xamide (I-26);
(S)-1'-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carbo-
xamide (I-27);
(R)-1'-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carbo-
xamide (I-28);
(S)-1'-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carbo-
xamide (I-29);
(R)-1'-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carb-
oxamide (I-30);
(S)-1'-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carb-
oxamide (I-31);
(R)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide (I-32);
(S)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide (I-33);
(R)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-
-carboxamide (I-34);
(S)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-
-carboxamide (I-35);
(R)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide (I-36);
(S)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide (I-37);
N-hydroxy-1'-methyl-5'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-ca-
rboxamide (I-38);
N-hydroxy-1'-methyl-6'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-car-
boxamide (I-39);
N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-5-car-
boxamide (I-40);
N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxamid-
e (I-41); and
N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,4'-piperidine]-5-carboxamid-
e (I-42).
50. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of and priority to U.S.
provisional application No. 62/351,399, filed Jun. 17, 2016, the
entire contents of which are incorporated herein by reference in
its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to inhibitors of
zinc-dependent histone deacetylases (HDACs) useful in the treatment
of diseases or disorders associated with HDACs including cell
proliferation diseases (e.g., cancer), neurological and
inflammatory diseases. Specifically, this invention is concerned
with compounds and compositions inhibiting HDACs, methods of
treating diseases associated with HDACs, and methods of
synthesizing these compounds.
BACKGROUND OF THE INVENTION
[0003] Many members of the HDAC family require zinc (Zn) to
function properly. For instance, the isozyme histone deacetylase 6
(HDAC6) is a zinc-dependent histone deacetylase that possesses
histone deacetylase activity. Other family members include HDACs
1-5 and 7-11. (De Ruijter et al., Biochem. J. 2003. 370;
737-749).
[0004] HDAC6 is known to deacetylate and associate with
.alpha.-tubulin, cortactin, heat shock protein 90, -catenin,
glucose-regulated protein 78 kDa, myosin heavy chain 9, heat shock
cognate protein 70, and dnaJ homolog subfamily A member 1 (reviewed
in Li et al., EBS J. 2013, 280: 775-93; Zhang et al., Protein Cell.
2015, 6(1): 42-54). Diseases in which HDAC6 inhibition could have a
potential benefit include cancer (reviewed in Aldana-Masangkay et
al., J. Biomed. Biotechnol. 2011, 875824), specifically: multiple
myeloma (Hideshima et al., Proc. Natl. Acad. Sci. USA 2005,
102(24):8567-8572); lung cancer (Kamemura et al., Biochem. Biophys.
Res. Commun. 2008, 374(1); 84-89); ovarian cancer (Bazzaro et al.,
Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et
al., Cancer Res. 2008, 68(18):7561-7569; Park et al., Oncol. Rep.
2011, 25: 1677-81; Rey et al., Eur. J. Cell Biol. 2011, 90:
128-35); prostate cancer (Seidel et al., Biochem. Pharmacol. 2015
(15)00714-5); pancreatic cancer (Nawrocki et al., Cancer Res. 2006,
66(7):3773-3781); renal cancer (Cha et al., Clin. Cancer Res. 2009,
15(3): 840-850); hepatocellular cancer (Ding et al., FEBS Lett.
2013, 587:880-6; Kanno et al., Oncol. Rep. 2012, 28: 867-73);
lymphomas (Ding et al., Cancer Cell Int. 2014, 14:139; Amengual et
al., Clin Cancer Res. 2015, 21(20):4663-75); and leukemias such as
acute myeloid leukemia (AML) (Fiskus et al., Blood 2008, 112(7);
2896-2905) and acute lymphoblastic leukemia (ALL)
(Rodriguez-Gonzalez et al., Blood 2008, 1 12(11): Abstract
1923)).
[0005] Inhibition of HDAC6 may also have a role in cardiovascular
disease, including pressure overload, chronic ischemia, and
infarction-reperfusion injury (Tannous et al., Circulation 2008, 1
17(24):3070-3078); bacterial infection, including those caused by
uropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem.
2008, 284(1):446-454); neurological diseases caused by accumulation
of intracellular protein aggregates such as Alzheimer's,
Parkinson's and Huntington's disease (reviewed in Simoes-Pires et
al., Mol. Neurodegener. 2013, 8: 7) or central nervous system
trauma caused by tissue injury, oxidative-stress induced neuronal
or axomal degeneration (Rivieccio et al., Proc. Natl. Acad. Sci.
USA 2009, 106(46):19599-195604); and inflammation and autoimmune
diseases through enhanced T cell-mediated immune tolerance at least
in part through effects on regulatory T cells, including rheumatoid
arthritis, psoriasis, spondylitis arthritis, psoriatic arthritis,
multiple sclerosis, lupus, colitis and graft versus host disease
(reviewed in Wang et al., Nat. Rev. Drug Disc. 2009 8(12):969-981;
Vishwakarma et al., Int. Immunopharmacol. 2013, 16:72-8; Kalin et
al., J. Med. Chem. 2012, 55:639-51); and fibrotic disease,
including kidney fibrosis (Choi et al., Vascul. Pharmacol. 2015
72:130-140).
[0006] Four HDAC inhibitors are currently approved for the
treatment of some cancers. These are suberanilohydroxamic acid
(Vorinostat; Zolinza.RTM.) for the treatment of cutaneous T cell
lymphoma and multiple myeloma; Romidepsin (FK228; FR901228;
Istodax.RTM.) for the treatment of peripheral T cell lymphoma;
Panobinostat (LBH-589; Farydak.RTM.) for the treatment of multiple
myeloma; and belinostat (PXD101; Beleodaq.RTM.) for the treatment
of peripheral T cell lymphoma. However, these drugs are of limited
effectiveness and can give rise to unwanted side effects. Thus
there is a need for HDAC inhibitors with an improved
safety-efficacy profile.
SUMMARY OF THE INVENTION
[0007] One aspect of the invention relates to compounds of Formula
I:
##STR00001##
[0008] and pharmaceutically acceptable salts, prodrugs, solvates,
hydrates, tautomers, or isomers thereof, wherein: [0009] X.sup.1,
X.sup.2, X.sup.3, X.sup.4, X.sup.5, and X.sup.6 are each
independently, at each occurrence, --CR.sup.1R.sup.2--,
--NR.sup.3--, --O--, --C(O)--, --S(O).sub.2--, --S(O)--, or --S--;
[0010] Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are each
independently, at each occurrence, N or CR.sup.1, wherein the
hydroxamic acid is attached at Y.sup.2 or Y.sup.3 and Y.sup.2 or
Y.sup.3 is a carbon atom when attached to the hydroxamic acid;
[0011] L is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--; [0012] R is independently --H,
--C.sub.1-C.sub.6alkyl, --C.sub.2-C.sub.6alkenyl,
--C.sub.4-C.sub.5cycloalkenyl, --C.sub.2-C.sub.6alkynyl,
--C.sub.3-C.sub.8cycloalkyl, --C.sub.5-C.sub.12spirocycloalkyl,
heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5
heteroatoms selected from the group consisting of N, S, P, or O,
wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl,
spirocycloalkyl, heterocyclyl, spiroheterocyclyl, aryl, or
heteroaryl is optionally substituted with one or more --OH,
halogen, oxo, --NO.sub.2, --CN, --R.sup.1, --R.sup.2, --SR.sup.3,
--OR.sup.3, --NHR.sup.3, --NR.sup.3R.sup.4,
--S(O).sub.2NR.sup.3R.sup.4, --S(O).sub.2R.sup.1, --C(O)R.sup.1,
--CO.sub.2R.sup.1, --NR.sup.3S(O).sub.2R.sup.1, --S(O)R.sup.1,
--S(O)NR.sup.3R.sup.4, --NR.sup.3S(O)R.sup.1, heterocyclyl, aryl,
or heteroaryl; [0013] R.sup.1 and R.sup.2 are independently, at
each occurrence, --H, --R.sup.3, --R.sup.4, --C.sub.1-C.sub.6alkyl,
--C.sub.2-C.sub.6alkenyl, --C.sub.4-C.sub.5cycloalkenyl,
--C.sub.2-C.sub.6alkynyl. --C.sub.3-C.sub.8cycloalkyl,
heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected
from the group consisting of N, S, P and O, --OH, halogen,
--NO.sub.2, --CN, --NHC.sub.1-C.sub.6alkyl,
--N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6alkyl).sub.2,
--N(C.sub.1-C.sub.6alkyl)S(O).sub.2R.sup.5,
--S(O).sub.2(C.sub.1-C.sub.6alkyl),
--(C.sub.1-C.sub.6alkyl)S(O).sub.2R.sup.5,
--C(O)C.sub.1-C.sub.6alkyl, --CO.sub.2C.sub.1-C.sub.6alkyl,
--N(C.sub.1-C.sub.6alkyl)S(O).sub.2C.sub.1-C.sub.6alkyl, or
--(CHR.sup.5).sub.pNR.sup.3R.sup.4, wherein each alkyl, alkenyl,
cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl is optionally substituted with one or more --OH,
halogen, --NO.sub.2, oxo, --CN, --R.sup.5, --OR.sup.3, --NHR.sup.3,
--NR.sup.3R.sup.4, --S(O).sub.2N(R.sup.3).sub.2--,
--S(O).sub.2R.sup.5, --C(O)R.sup.5, --CO.sub.2R.sup.5,
--NR.sup.3S(O).sub.2R.sup.5, --S(O)R.sup.5, --S(O)NR.sup.3R.sup.4,
--NR.sup.3S(O)R.sup.5, heterocyclyl, aryl, or heteroaryl; [0014] or
R.sup.1 and R.sup.2 can combine with the carbon atom to which they
are both attached to form a cycloalkyl, heterocycle,
spirocycloalkyl, spiroheterocycle, or spirocycloalkenyl; [0015] or
R.sup.1 and R.sup.2, when on adjacent or non-adjacent atoms, can
combine to form a heterocycle, cycloalkyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, or cycloalkenyl; [0016] R.sup.3 and R.sup.4 are
independently, at each occurrence, --H, --C.sub.1-C.sub.6alkyl,
--C.sub.2-C.sub.6alkenyl, --C.sub.4-C.sub.8cycloalkenyl,
--C.sub.2-C.sub.6alkynyl, --C.sub.3-C.sub.8cycloalkyl,
heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected
from N, S, P, and O, --S(O).sub.2N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2(C.sub.1-C.sub.6alkyl),
--(C.sub.1-C.sub.6alkyl)S(O).sub.2R.sup.5,
--C(O)C.sub.1-C.sub.6alkyl, --CO.sub.2C.sub.1-C.sub.6alkyl, or
--(CHR.sup.5).sub.pN(C.sub.1-C.sub.6alkyl).sub.2, wherein each
alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl,
aryl, and heteroaryl is optionally substituted with one or more
substituents selected from --OH, halogen, --NO.sub.2, oxo, --CN,
--R.sup.5, --O(C.sub.1-C.sub.6)alkyl, --NH(C.sub.1-C.sub.6)alkyl,
--N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2NHC.sub.1-C.sub.6alkyl, --C(O)C.sub.1-C.sub.6alkyl,
--CO.sub.2C.sub.1-C.sub.6alkyl,
--N(C.sub.1-C.sub.6alkyl)S(O).sub.2C.sub.1-C.sub.6alkyl,
--S(O)R.sup.5, --S(O)N(C.sub.1-C.sub.6alkyl).sub.2,
--N(C.sub.1-C.sub.6alkyl)S(O)R.sup.5, heterocyclyl, aryl, or
heteroaryl; [0017] R.sup.5 is independently, at each occurrence,
--H, --C.sub.1-C.sub.6alkyl, --C.sub.2-C.sub.6alkenyl,
--C.sub.4-C.sub.8cycloalkenyl, --C.sub.2-C.sub.6alkynyl,
--C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from N, S, P and O, --OH,
halogen, --NO.sub.2, --CN, --NHC.sub.1-C.sub.6alkyl,
--N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2NH(C.sub.1-C.sub.6alkyl),
--S(O).sub.2N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2C.sub.1-C.sub.6alkyl, --C(O)C.sub.1-C.sub.6alkyl,
--CO.sub.2C.sub.1-C.sub.6alkyl,
--N(C.sub.1-C.sub.6alkyl)SO.sub.2C.sub.1-C.sub.6alkyl,
--S(O)(C.sub.1-C.sub.6alkyl), --S(O)N(C.sub.1-C.sub.6alkyl).sub.2,
--N(C.sub.1-C.sub.6alkyl)S(O)(C.sub.1-C.sub.6alkyl) or
--(CH.sub.2).sub.pN(C.sub.1-C.sub.6alkyl).sub.2; [0018] p is 0, 1,
2, 3, 4, 5, or 6; [0019] n is 0, 1, 2, 3, or 4; [0020] m is 0, 1,
or 2; and [0021] wherein the sum m+n.ltoreq.4.
[0022] Another aspect of the invention relates to a method of
treating a disease or disorder associated with HDAC6 modulation in
a subject in need thereof, comprising administering to the subject
an effective amount of a compound of Formula I.
[0023] Another aspect of the invention is directed to a method of
inhibiting a histone deacetylase (e.g., a zinc-dependent histone
deacetylase such as HDAC6). The method involves administering to a
patient in need thereof an effective amount of a compound of
Formula I. In some embodiments, the method of treating a disease or
disorder associated with HDAC6 modulation in a subject includes
inhibiting a histone deacetylase (e.g., a zinc-dependent histone
deacetylase such as HDAC6) in the subject.
[0024] Another aspect of the invention is directed to
pharmaceutical compositions comprising a compound of Formula I and
a pharmaceutically acceptable carrier. The pharmaceutically
acceptable carrier can further include an excipient, diluent, or
surfactant. The pharmaceutical composition can be effective for
treating a disease or disorder associated with HDAC6 modulation in
a subject in need thereof. The pharmaceutical compositions can
comprise the compounds of the present invention for use in treating
diseases described herein. The compositions can contain at least
one compound of the invention and a pharmaceutically acceptable
carrier.
[0025] Another aspect of the present disclosure relates to a
compound of Formula I, or a pharmaceutically acceptable salt,
hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for
use in treating or preventing a disease associated with HDAC6
modulation. The invention also provides the use of the compounds
described herein in the manufacture of a medicament for the
treatment of a disease associated with HDACs.
[0026] The present invention also provides methods for the
treatment of human diseases or disorders including, without
limitation, oncological, neurological, inflammatory, autoimmune,
infectious, metabolic, hematologic, or cardiovascular diseases or
disorders.
[0027] The present invention also provides compounds that are
useful in inhibiting of zinc-dependent HDAC enzymes, for instance
HDAC6. These compounds can also be useful in the treatment of
diseases including cancer.
[0028] The present invention further provides compounds that can
inhibit HDAC6. In some embodiments, the efficacy-safety profile of
the compounds of the current invention can be improved relative to
other known HDAC (e.g. HDAC6) inhibitors. Additionally, the present
technology also has the advantage of being able to be used for a
number of different types of diseases, including cancer and
non-cancer indications. Additional features and advantages of the
present technology will be apparent to one of skill in the art upon
reading the Detailed Description of the Invention, below.
DETAILED DESCRIPTION OF THE INVENTION
[0029] HDAC6 is a zinc-dependent histone deacetylase that has two
catalytic domains. HDAC6 can interact with and deacetylate
non-histone proteins, including HSP90 and .alpha.-tubulin.
Acetylation of HSP90 is associated with loss of function of HSP90.
HDAC6 is also implicated in the degradation of misfolded proteins
as part of the aggresome. Accordingly, inhibition of HDAC6 can have
downstream effects that can play a role in the development of
certain diseases such as cancer. The present invention provides
inhibitors of HDAC6 and methods for using the same to treat
disease.
[0030] In a first aspect of the invention, compounds of Formula I
are described:
##STR00002##
and pharmaceutically acceptable salts, prodrugs, solvates,
hydrates, tautomers, and isomers thereof, wherein Y.sup.1, Y.sup.2,
Y.sup.3, Y.sup.4, X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5,
X.sup.6, L, R, m and n are described as above.
[0031] The details of the invention are set forth in the
accompanying description below. Although methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present invention, illustrative methods
and materials are now described. Other features, objects, and
advantages of the invention will be apparent from the description
and from the claims. In the specification and the appended claims,
the singular forms also include the plural unless the context
clearly dictates otherwise. Unless defined otherwise, all technical
and scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which this
invention belongs. All patents and publications cited in this
specification are incorporated herein by reference in their
entireties.
Definitions
[0032] The articles "a" and "an" are used in this disclosure to
refer to one or more than one (i.e., to at least one) of the
grammatical object of the article. By way of example, "an element"
means one element or more than one element.
[0033] The term "and/or" is used in this disclosure to mean either
"and" or "or" unless indicated otherwise.
[0034] The term "optionally substituted" is understood to mean that
a given chemical moiety (e.g. an alkyl group) can (but is not
required to) be bonded other substituents (e.g. heteroatoms). For
instance, an alkyl group that is optionally substituted can be a
fully saturated alkyl chain (i.e. a pure hydrocarbon).
Alternatively, the same optionally substituted alkyl group can have
substituents different from hydrogen. For instance, it can, at any
point along the chain be bonded to a halogen atom, a hydroxyl
group, or any other substituent described herein. Thus the term
"optionally substituted" means that a given chemical moiety has the
potential to contain other functional groups, but does not
necessarily have any further functional groups.
[0035] The term "aryl" refers to cyclic, aromatic hydrocarbon
groups that have 1 to 2 aromatic rings, including monocyclic or
bicyclic groups such as phenyl, biphenyl or naphthyl. Where
containing two aromatic rings (bicyclic, etc.), the aromatic rings
of the aryl group may be joined at a single point (e.g., biphenyl),
or fused (e.g., naphthyl). The aryl group may be optionally
substituted by one or more substituents, e.g., 1 to 5 substituents,
at any point of attachment. Exemplary substituents include, but are
not limited to, --H, -halogen, --O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl, --OC.sub.2-C.sub.6alkenyl,
--OC.sub.2-C.sub.6alkynyl, --C.sub.2-C.sub.6alkenyl,
--C.sub.2-C.sub.6alkynyl, --OH, --OP(O)(OH).sub.2,
--OC(O)C.sub.1-C.sub.6alkyl, --C(O)C.sub.1-C.sub.6alkyl,
--OC(O)OC.sub.1-C.sub.6alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.6alkyl), --N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2--C.sub.1-C.sub.6alkyl, --S(O)NHC.sub.1-C.sub.6alkyl,
and --S(O)N(C.sub.1-C.sub.6alkyl).sub.2. The substituents can
themselves be optionally substituted. Furthermore when containing
two fused rings the aryl groups herein defined may have an
unsaturated or partially saturated ring fused with a fully
saturated ring. Exemplary ring systems of these aryl groups include
indanyl, indenyl, tetrahydronaphthalenyl, and
tetrahydrobenzoannulenyl.
[0036] Unless otherwise specifically defined, "heteroaryl" means a
monovalent monocyclic aromatic radical or a polycyclic aromatic
radical of 5 to 24 ring atoms, containing one or more ring
heteroatoms selected from N, S, P, and O, the remaining ring atoms
being C. Heteroaryl as herein defined also means a bicyclic
heteroaromatic group wherein the heteroatom is selected from N, S,
P, and O. The aromatic radical is optionally substituted
independently with one or more substituents described herein.
Examples include, but are not limited to, furyl, thienyl, pyrrolyl,
pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl,
oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl,
benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,
benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,
imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl,
imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl,
pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl,
thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl,
thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl,
indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,
benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,
dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,
1,6-naphthyridinyl, benzo[de]isoquinolinyl,
pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl,
quinazolinyl, tetrazolo[1,5-a]pyridinyl,
[1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,
pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,
pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,
pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,
3,4-dihydro-2H-1.lamda..sup.2-pyrrolo[2,1-b]pyrimidine,
dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl,
furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4] thiazinyl,
benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl,
benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine,
[1,2,4]triazolo[1,5-a]pyridinyl, benzo [1,2,3]triazolyl,
imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,
benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole,
1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo
[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl,
thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl,
thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof.
Furthermore when containing two fused rings the heteroaryl groups
herein defined may have an unsaturated or partially saturated ring
fused with a fully saturated ring. Exemplary ring systems of these
heteroaryl groups include indolinyl, indolinonyl,
dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl,
thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine,
3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl,
indolyl, and dihydrobenzoxanyl.
[0037] "Alkyl" refers to a straight or branched chain saturated
hydrocarbon. C.sub.1-C.sub.6alkyl groups contain 1 to 6 carbon
atoms. Examples of a C.sub.1-C.sub.6alkyl group include, but are
not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl,
isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.
[0038] The term "alkenyl" means an aliphatic hydrocarbon group
containing a carbon-carbon double bond and which may be straight or
branched having about 2 to about 6 carbon atoms in the chain.
Certain alkenyl groups have 2 to about 4 carbon atoms in the chain.
Branched means that one or more lower alkyl groups such as methyl,
ethyl, or propyl are attached to a linear alkenyl chain. Exemplary
alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl.
A C.sub.2-C.sub.6 alkenyl group is an alkenyl group containing
between 2 and 6 carbon atoms.
[0039] The term "alkynyl" means an aliphatic hydrocarbon group
containing a carbon-carbon triple bond and which may be straight or
branched having about 2 to about 6 carbon atoms in the chain.
Certain alkynyl groups have 2 to about 4 carbon atoms in the chain.
Branched means that one or more lower alkyl groups such as methyl,
ethyl, or propyl are attached to a linear alkynyl chain. Exemplary
alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl,
3-methylbutynyl, and n-pentynyl. A C.sub.2-C.sub.6 alkynyl group is
an alkynyl group containing between 2 and 6 carbon atoms.
[0040] The term "cycloalkyl" means monocyclic or polycyclic
saturated carbon rings containing 3-18 carbon atoms. Examples of
cycloalkyl groups include, without limitations, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl,
norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or
bicyclo[2.2.2]octenyl. A C.sub.3-C.sub.8 cycloalkyl is a cycloalkyl
group containing between 3 and 8 carbon atoms. A cycloalkyl group
can be fused (e.g., decalin) or bridged (e.g., norbornane).
[0041] The term "cycloalkenyl" means monocyclic, non-aromatic
unsaturated carbon rings containing 4-18 carbon atoms. Examples of
cycloalkenyl groups include, without limitation, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl. A
C.sub.4-C.sub.8 cycloalkenyl is a cycloalkenyl group containing
between 4 and 8 carbon atoms.
[0042] The terms "heterocyclyl" or "heterocycloalkyl" or
"heterocycle" refer to monocyclic or polycyclic 3 to 24-membered
rings containing carbon and heteroatoms taken from oxygen,
phosphorous nitrogen, or sulfur and wherein there is not
delocalized n electrons (aromaticity) shared among the ring carbon
or heteroatoms. Heterocyclyl rings include, but are not limited to,
oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,
oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,
tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,
thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl
S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl,
and homotropanyl. A heteroycyclyl or heterocycloalkyl ring can also
be fused or bridged, e.g., can be a bicyclic ring.
[0043] As used herein, the term "halo" or "halogen" means a fluoro,
chloro, bromo, or iodo group.
[0044] The term "carbonyl" refers to a functional group composing a
carbon atom double-bonded to an oxygen atom. It can be abbreviated
herein as C(O), or as C.dbd.O.
[0045] The term "oxo" refers to an oxygen atom that is
double-bonded to another atom. An "oxo" group can be connected to a
carbon atom (e.g., to form a carbonyl, as defined above) or can be
connected to a heteroatom such as sulfur (e.g., to form a sulfoxide
or a sulfone) or phosphorous (e.g., to form a phosphorous
ylide).
[0046] "Spirocycle" means carbogenic bicyclic ring systems with
both rings connected through a single atom. A "spirocycloalkyl" or
"spirocyclic" system is a spirocycle in which both rings are fully
carbogenic. The ring can be different in size and nature, or
identical in size and nature. Examples include spiropentane,
spirohexane, spiroheptane, spirooctane, spirononane, or
spirodecane. One or both of the rings in a spirocycle can be fused
to another carbocyclic, heterocyclic, aromatic, or heteroaromatic
ring. One or more of the carbon atoms in the spirocycle can be
substituted with a heteroatom (e.g., O, N, S, or P). A
C.sub.5-C.sub.12 spirocycle is a spirocycle containing between 5
and 12 carbon atoms. One or more of the carbon atoms can be
substituted with a heteroatom.
[0047] The term "spirocyclic heterocycle" "spiroheterocyclyl" or
"spiroheterocycle" is understood to mean a spirocycle wherein at
least one of the rings is a heterocycle (e.g., at least one of the
rings is furanyl, morpholinyl, or piperadinyl). A spirocyclic
heterocycle can contain between 5 and 12 atoms, at least one of
which is a heteroatom selected from N, O, S and P.
Spiroheterocycloalkyl groups can be for instance, without
limitation, azapiroheptanes; azaspirooctanes; azaspirononanes;
azaspirodecanes; oxaspiroheptanes; oxaspirooctanes;
octaspirononanes; or oxaspirodecanes.
[0048] The disclosure also includes pharmaceutical compositions
comprising an effective amount of a disclosed compound and a
pharmaceutically acceptable carrier. Representative
"pharmaceutically acceptable salts" include, e.g., water-soluble
and water-insoluble salts, such as the acetate, amsonate
(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,
bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate,
calcium, calcium edetate, camsylate, carbonate, chloride, citrate,
clavulariate, dihydrochloride, edetate, edisylate, estolate,
esylate, fiunarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexafluorophosphate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, sethionate, lactate, lactobionate, laurate, magnesium,
malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate,
pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate),
pantothenate, phosphate/diphosphate, picrate, polygalacturonate,
propionate, p-toluenesulfonate, salicylate, stearate, subacetate,
succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate salts.
[0049] The term "tautomers" refers to a set of compounds that have
the same number and type of atoms, but differ in bond connectivity
and are in equilibrium with one another. A "tautomer" is a single
member of this set of compounds. Typically a single tautomer is
drawn but it is understood that this single structure is meant to
represent all possible tautomers that might exist. Examples include
enol-ketone tautomerism. When a ketone is drawn it is understood
that both the enol and ketone forms are part of the invention.
[0050] The term "prodrug," as used in this disclosure, means a
compound which is convertible in vivo by metabolic means (e.g., by
hydrolysis) to a disclosed compound. Furthermore, as used herein a
prodrug is a drug which is inactive in the body, but is transformed
in the body typically either during absorption or after absorption
from the gastrointestinal tract into the active compound. The
conversion of the prodrug into the active compound in the body may
be done chemically or biologically (i.e., using an enzyme).
[0051] The term "solvate" refers to a complex of variable
stoichiometry formed by a solute and solvent. Such solvents for the
purpose of the invention may not interfere with the biological
activity of the solute. Examples of suitable solvents include, but
are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein
water is the solvent molecule are typically referred to as
hydrates. Hydrates include compositions containing stoichiometric
amounts of water, as well as compositions containing variable
amounts of water.
[0052] The term "isomer" refers to compounds that have the same
composition and molecular weight but differ in physical and/or
chemical properties. The structural difference may be in
constitution (geometric isomers) or in the ability to rotate the
plane of polarized light (stereoisomers). With regard to
stereoisomers, the compounds of Formula I may have one or more
asymmetric carbon atom and may occur as racemates, racemic mixtures
and as individual enantiomers or diastereomers.
[0053] The term "stereoisomers" refers to the set of compounds
which have the same number and type of atoms and share the same
bond connectivity between those atoms, but differ in three
dimensional structure. The term "stereoisomer" refers to any member
of this set of compounds. For instance, a stereoisomer may be an
enantiomer or a diastereomer.
[0054] The term "enantiomers" refers to a pair of stereoisomers
which are non-superimposable mirror images of one another. The term
"enantiomer" refers to a single member of this pair of
stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair
of enantiomers.
[0055] The term "diastereomers" refers to the set of stereoisomers
which cannot be made superimposable by rotation around single
bonds. For example, cis- and trans-double bonds, endo- and
exo-substitution on bicyclic ring systems, and compounds containing
multiple stereogenic centers with different relative configurations
are considered to be diastereomers. The term "diastereomer" refers
to any member of this set of compounds. In some examples presented,
the synthetic route may produce a single diastereomer or a mixture
of diastereomers. In some cases these diastereomers were separated
and in other cases a wavy bond is used to indicate the structural
element where configuration is variable.
[0056] An "effective amount" when used in connection with a
compound is an amount effective for treating or preventing a
disease in a subject as described herein.
[0057] The term "carrier", as used in this disclosure, encompasses
carriers, excipients, and diluents and means a material,
composition or vehicle, such as a liquid or solid filler, diluent,
excipient, solvent or encapsulating material, involved in carrying
or transporting a pharmaceutical agent from one organ, or portion
of the body, to another organ, or portion of the body of a
subject.
[0058] The term "treating" with regard to a subject, refers to
improving at least one symptom of the subject's disorder. Treating
includes curing, improving, or at least partially ameliorating the
disorder.
[0059] The term "disorder" is used in this disclosure to mean, and
is used interchangeably with, the terms disease, condition, or
illness, unless otherwise indicated.
[0060] The term "administer", "administering", or "administration"
as used in this disclosure refers to either directly administering
a disclosed compound or pharmaceutically acceptable salt of the
disclosed compound or a composition to a subject, or administering
a prodrug derivative or analog of the compound or pharmaceutically
acceptable salt of the compound or composition to the subject,
which can form an equivalent amount of active compound within the
subject's body.
[0061] A "patient" or "subject" is a mammal, e.g., a human, mouse,
rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate,
such as a monkey, chimpanzee, baboon or rhesus.
[0062] In one or more embodiments of the compounds of Formula I, n
is 0 and m is 1.
[0063] In one or more embodiments of the compounds of Formula I, n
is 1 and m is 1.
[0064] In one or more embodiments of the compounds of Formula I,
X.sup.5 is C(O).
[0065] In one or more embodiments of the compounds of Formula I, L
is a bond. In one or more embodiments, L is
--(CR.sup.1R.sup.2).sub.p--. In one or more embodiments, L is
--C(O)NR.sup.3--. In one or more embodiments, L is --S(O).sub.2--.
In one or more embodiments, L is --S(O).sub.2NR.sup.3--. In one or
more embodiments, L is --S(O)--. In one or more embodiments, L is
--S(O)NR.sup.3--. In one or more embodiments, L is
--C(O)(CR.sup.1R.sup.2).sub.pO--. In one or more embodiments, L is
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0066] In one or more embodiments of the compounds of Formula I,
the compound is of the Formula IA:
##STR00003##
[0067] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2-- and X.sup.2 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and
X.sup.3 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2-- and
X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0068] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0069] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0070] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --NH--. In one or more embodiments, X.sup.1 is --NH--
and X.sup.2 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--NH--, X.sup.2 is --CH.sub.2--, and X.sup.3 is --CH.sub.2--. In
one or more embodiments, X.sup.1 is --NH--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2-- and X.sup.4 is --CH.sub.2--.
In one or more embodiments, X.sup.1 is --NH--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2-- and
X.sup.5 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --NH--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or
more embodiments, X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--.
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --NH--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is --NH--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0071] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is --NH--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --NH--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --NH--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1
and n is 1. In any of the above-embodiments, L is a bond.
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0072] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--. X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0073] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --O--. In one or more embodiments, X.sup.1 is --O-- and
X.sup.2 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--O--, X.sup.2 is --CH.sub.2--, and X.sup.3 is --CH.sub.2--. In one
or more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2-- and X.sup.4 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --CH.sub.2--.
In one or more embodiments, X.sup.1 is --O--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.4 is --CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and
m is 0. In one or more embodiments, X.sup.1 is --O--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 0 and n is 0. In one or more embodiments, X.sup.1 is --O--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In
one or more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
2. In one or more embodiments, X.sup.1 is --O--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0074] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--O--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0075] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond. --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0076] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --C(O)--. In one or more embodiments, X.sup.1 is
--C(O)-- and X.sup.2 is --CH.sub.2--. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2-- and X.sup.4 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3
is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--
and X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--C(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one
or more embodiments, X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --C(O)--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0077] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1
and n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0078] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0079] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --S(O).sub.2--. In one or more embodiments, X.sup.1 is
--S(O).sub.2-- and X.sup.2 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--,
and X.sup.3 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--
and X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or more
embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --S(O).sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or more
embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0
and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0080] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0081] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0082] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --S(O)--. In one or more embodiments, X.sup.1 is
--S(O)-- and X.sup.2 is --CH.sub.2--. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2-- and X.sup.4 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3
is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--
and X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--S(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one
or more embodiments, X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --S(O)--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0083] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1
and n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0084] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)CR.sup.1R.sup.2).sub.p--.
[0085] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --S--. In one or more embodiments, X.sup.1 is --S-- and
X.sup.2 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--S--, X.sup.2 is --CH.sub.2--, and X.sup.3 is --CH.sub.2--. In one
or more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2-- and X.sup.4 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --CH.sub.2--.
In one or more embodiments, X.sup.1 is --S--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and
m is 0. In one or more embodiments, X.sup.1 is --S--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 0 and n is 0. In one or more embodiments, X.sup.1 is --S--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In
one or more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
2. In one or more embodiments, X.sup.1 is --S--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0086] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--S--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0087] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2)P--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0088] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2-- and X.sup.2 is --NH--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, and
X.sup.3 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --CH.sub.2-- and
X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--,
X.sup.4 is --CH.sub.2--, X is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--NH--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3-,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0089] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--,
m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --CH.sub.2--, X.sup.4
is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is
1 and n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0090] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0091] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2-- and X.sup.2 is --O--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, and X.sup.3
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2-- and X.sup.4
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --O--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--O--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
2. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--O--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In
any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0092] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0093] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0094] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2-- and X.sub.2 is --C(O)--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, and
X.sup.3 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --CH.sub.2-- and
X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3
is --CH.sub.1--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--
and X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.1 is --CH.sub.2--, m is 0 and n is 0. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0095] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--,
m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --C(O)--, X.sup.1 is --CH.sub.2--, X.sup.1 is --CH.sub.2--, m is
1 and n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0096] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is
--CH.sub.2--. X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0097] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2-- and X.sup.2 is --S(O).sub.2--. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S(O).sub.2--, and X.sup.3 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--,
X.sup.3 is --CH.sub.2-- and X.sup.4 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --S(O).sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is --CH.sub.2--.
In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0
and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0098] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.1 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0099] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0100] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2-- and X.sup.2 is --S(O)--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O--, and
X.sup.3 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --CH.sub.2-- and
X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3
is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--
and X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0101] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--,
m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is
1 and n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0102] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0103] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2-- and X.sup.2 is --S--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, and X.sup.3
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2-- and X.sup.4
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S--, X.sup.4 is --CH.sub.2--, X.sup.2 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
2. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In
any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0104] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0105] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond. --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0106] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--NH--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --NH-- and X.sup.4 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --NH--, X.sup.4 is --CH.sub.2--
and X.sup.5 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --NH--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is
--CH.sub.2--. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0107] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--NH--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --NH--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --NH--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --NH--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0108] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--NH--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.1 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.3 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--NH--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0109] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--O--. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2
is --CH.sub.2--, X.sup.3 is --O-- and X.sup.4 is --CH.sub.2--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --O--, X.sup.4 is --CH.sub.2-- and X.sup.5
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --O--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is --CH.sub.2--.
In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0110] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --O--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --O--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --O--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --O--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0111] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --O--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --O--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0112] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--S--. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2
is --CH.sub.2--, X.sup.3 is --S-- and X.sup.4 is --CH.sub.2--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --S--, X.sup.4 is --CH.sub.2-- and X.sup.5
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is --CH.sub.2--.
In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0113] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--.
X.sup.3 is --S--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0114] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.1 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0115] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--C(O)--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)-- and X.sup.4 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0116] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0117] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0118] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--S(O).sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O).sub.2--
and X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O).sub.2--,
X.sup.4 is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In any of the
above-embodiments, L is a bond. --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0119] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O).sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O).sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0120] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of
the above-embodiments, L is a bond. --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0121] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--S(O)--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O)-- and X.sup.4 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O)--, X.sup.4 is
--CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0122] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S(O)--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0123] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0124] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --NH--. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --NH-- and X.sup.5 is --CH.sub.2--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --NH--, X.sup.5
is --CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --NH--, X.sup.5 is
--CH.sub.2--, m is 0 and n is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--NH--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --NH--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--NH--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n
is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0125] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --NH--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.1 is --C(O)--, X.sup.4 is --NH--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0126] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --NH--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0127] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --O--. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --O-- and X.sup.5 is --CH.sub.2--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --O--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --O--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --O--, X.sup.5 is --CH.sub.2--,
m is 0 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --O--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --O--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --O--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --O--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0128] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --O--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --O--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --O--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --O--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0129] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --O--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --O--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --O--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0130] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --S--. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S-- and X.sup.5 is --CH.sub.2--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --S--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --S--, X.sup.5 is --CH.sub.2--,
m is 0 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --S--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --S--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0131] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --S--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --S--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --S--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0132] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --S--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0133] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --C(O)--. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)-- and X.sup.5 is --CH.sub.2--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, m is 0 and n is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--,
m is 0 and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0134] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0135] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0136] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --S(O).sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O).sub.2-- and X.sup.5 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--S(O).sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S(O).sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is
0. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S(O).sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--S(O).sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --S(O).sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In
any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0137] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH-- and m is 1. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --S(O).sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is
0. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O).sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --S(O).sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O).sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is
1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3-,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0138] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --S(O).sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0139] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --S(O)--. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O)-- and X.sup.5 is --CH.sub.2--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5
is --CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5
is --CH.sub.2--, m is 0 and n is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--S(O)--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and
n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0140] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --S(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0141] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0142] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --NH--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --NH-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --NH--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--NH--, m is 0 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --NH--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --NH--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --NH--, X.sup.6 is --CH.sub.2--, m is 0
and n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --NH--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.pO--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0143] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --NH--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --NH--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --NH--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --NH--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --NH--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0144] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --NH--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --NH--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond. --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0145] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --O--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --O-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --O--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --O--,
m is 0 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --O--, X.sup.1 is --CH.sub.2--, m is 0 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --O--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --O--, X.sup.6 is --CH.sub.2--, m is 0 and
n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --O--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0146] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --O--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --O--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --O--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --O--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --O--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0147] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --O--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --O--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0148] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --S--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S--,
m is 0 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --S--, X.sup.6 is --CH.sub.2--, m is 0 and
n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3-, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0149] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --S--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0150] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0151] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --C(O)--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, m is 0 and n is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and
n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0152] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.5
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --C(O)--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0153] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0154] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is
--S(O).sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2-- and X.sup.6 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--S(O).sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--, m is 0 and n is
0. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --S(O).sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --S(O).sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S(O).sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
2. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S(O).sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4; is --CH.sub.2--, X.sup.6 is --S(O).sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)CR.sup.1R.sup.2).sub.pO--, or
--C(O)CR.sup.1R.sup.2).sub.p--.
[0155] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--S(O).sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any
of the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0156] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--S(O).sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--S(O).sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any
of the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0157] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --S(O)--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S(O)-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S(O)--, m is 0 and n is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is --CH.sub.2--, m is 0
and n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0158] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S(O)--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --S(O)--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S(O)--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0159] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0160] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --NH--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --NH-- and m is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--NH--, m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --NH--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --NH--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --NH--, m is 0 and n is 2. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --NH--, m is 0 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --NH--, m is 0 and n is 2. In any
of the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3-, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(OX(R.sup.1R.sup.2).sub.p--.
[0161] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --NH-- and m is 1. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--NH--, m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --NH--, m is 1
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --NH--, m is 1 and n
is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0162] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --NH--, m is 1 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--NH--, m is 1 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--NH--, m is 1 and n is 2. In any of the above-embodiments, L is a
bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0163] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --O--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --O-- and m is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--,
m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --O--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --O--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --O--, m is 0 and n is 2. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --O--, m is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --O--, m is 0 and n is 2. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0164] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.5 is --O-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--,
m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--, m is 1
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--, m is 1 and n
is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0165] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --O--, m is 1 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--, m is 1
and n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--, m is 1 and
n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O)--,
--S(O).sub.zNR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0166] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --C(O)--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --C(O)-- and m is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--C(O)--, m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --C(O)--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --C(O)--,
m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --C(O)--, m is 0 and n is 2. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --C(O)--, m is 0 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --C(O)--, m is 0 and n is 2. In any
of the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O)--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0167] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --C(O)-- and m is 1. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--C(O)--, m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --C.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --C(O)--, m is
1 and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --C(O)--, m is 1 and
n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0168] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --C(O)--, m is 1 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--C(O)--, m is 1 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--C(O)--, m is 1 and n is 2. In any of the above-embodiments, L is
a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3-,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0169] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --S(O).sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --S(O).sub.2-- and m is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S(O).sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S(O).sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --S(O).sub.2--, m is
0 and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --S(O).sub.2--, m is 0 and n is 2. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --S(O).sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --S(O).sub.2--, m is
0 and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0170] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S(O).sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S(O).sub.2--, m is 1 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --S(O).sub.2--, m is 1 and n is 1. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --S(O).sub.2--, m is 1 and n is 1. In
any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0171] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --S(O).sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --S(O).sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S(O).sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0172] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --S(O)--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --S(O)-- and m is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S(O)--, m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --S(O)--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --S(O)--,
m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --S(O)--, m is 0 and n is 2. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --S(O)--, m is 0 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --S(O)--, m is 0 and n is 2. In any
of the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0173] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S(O)-- and m is 1. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S(O)--, m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S(O)--, m is
1 and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S(O)--, m is 1 and
n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0174] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --S(O)--, m is 1 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S(O)--, m is 1 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S(O)--, m is 1 and n is 2. In any of the above-embodiments, L is
a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0175] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --S--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --S-- and m is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--,
m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --S--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --S--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --S--, m is 0 and n is 2. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --S--, m is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --S--, m is 0 and n is 2. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0176] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--,
m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--, m is 1
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--, m is 1 and n
is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0177] In one or more embodiments of the compounds of Formula IA,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --S--, m is 1 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--, m is 1
and n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--, m is 1 and
n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0178] In one or more embodiments of the compounds of Formula IA,
the compound is of the formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6,
IA-7, or IA-8:
##STR00004##
[0179] In one or more embodiments, of the compounds of Formula I,
the compound is of the Formula IB:
##STR00005##
[0180] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2-- and X.sup.2 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and
X.sup.3 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2- and
X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0181] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0182] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0183] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --NH--. In one or more embodiments, X.sup.1 is --NH--
and X.sup.2 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--NH--, X.sup.2 is --CH.sub.2--, and X.sup.3 is --CH.sub.2--. In
one or more embodiments, X.sup.1 is --NH--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2- and X.sup.4 is --CH.sub.2--.
In one or more embodiments, X.sup.1 is --NH--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2-- and
X.sup.5 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --NH--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or
more embodiments, X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--.
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --NH--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is --NH--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0184] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is --NH--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --NH--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --NH--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1
and n is 1. In any of the above-embodiments, L is a bond.
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0185] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --NH--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0186] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --O--. In one or more embodiments, X.sup.1 is --O-- and
X.sup.2 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--O--, X.sup.2 is --CH.sub.2--, and X.sup.3 is --CH.sub.2--. In one
or more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2-- and X.sup.4 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --CH.sub.2--.
In one or more embodiments, X.sup.1 is --O--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and
m is 0. In one or more embodiments, X.sup.1 is --O--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 0 and n is 0. In one or more embodiments, X.sup.1 is --O--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In
one or more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
2. In one or more embodiments, X.sup.1 is --O--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0187] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--O--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0188] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --O--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond. --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0189] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --C(O)--. In one or more embodiments, X.sup.1 is
--C(O)-- and X.sup.2 is --CH.sub.2--. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2-- and X.sup.4 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3
is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--
and X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--C(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one
or more embodiments, X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --C(O)--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0190] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --C(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1
and n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0191] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --C(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0192] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --S(O).sub.2--. In one or more embodiments, X.sup.1 is
--S(O).sub.2-- and X.sup.2 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--,
and X.sup.3 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--
and X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or more
embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.1 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --S(O).sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or more
embodiments, X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0
and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0193] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0194] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S(O).sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0195] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --S(O)--. In one or more embodiments, X.sup.1 is
--S(O)-- and X.sup.2 is --CH.sub.2--. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2-- and X.sup.4 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3
is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--
and X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--S(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one
or more embodiments, X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --S(O)--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0196] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is --S(O)--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1
and n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0197] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S(O)--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)CR.sup.1R.sup.2).sub.p--.
[0198] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --S--. In one or more embodiments, X.sup.1 is --S-- and
X.sup.2 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--S--, X.sup.2 is --CH.sub.2--, and X.sup.3 is --CH.sub.2--. In one
or more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2-- and X.sup.4 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --CH.sub.2--.
In one or more embodiments, X.sup.1 is --S--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and
m is 0. In one or more embodiments, X.sup.1 is --S--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 0 and n is 0. In one or more embodiments, X.sup.1 is --S--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In
one or more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
2. In one or more embodiments, X.sup.1 is --S--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0199] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--S--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --S--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sup.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0200] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --S--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2)P--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0201] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2-- and X.sup.2 is --NH--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, and
X.sup.3 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --CH.sub.2-- and
X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--NH--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0202] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--,
m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --CH.sub.2--, X.sup.4
is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is
1 and n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0203] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --NH--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0204] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2-- and X.sup.2 is --O--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, and X.sup.3
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2-- and X.sup.4
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --O--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--O--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
2. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--O--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In
any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0205] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --O--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0206] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --O--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0207] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2-- and X.sub.2 is --C(O)--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, and
X.sup.3 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --CH.sub.2-- and
X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3
is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--
and X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0208] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--,
m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is
1 and n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0209] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sub.2 is --C(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3-, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0210] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2-- and X.sup.2 is --S(O).sub.2--. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S(O).sub.2--, and X.sup.3 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--,
X.sup.3 is --CH.sub.2-- and X.sup.4 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --S(O).sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is --CH.sub.2--.
In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S(O).sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0211] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0212] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O).sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0213] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2-- and X.sup.2 is --S(O)--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, and
X.sup.3 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --CH.sub.2-- and
X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3
is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--
and X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.1 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0214] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--,
m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --CH.sub.2--, X.sup.4
is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is
1 and n is 1. In any of the above-embodiments, L is a bond.
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0215] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S(O)--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0216] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2-- and X.sup.2 is --S--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, and X.sup.3
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2-- and X.sup.4
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.4 is --C(O)--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
1. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
2. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--S--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In
any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0217] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --S--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0218] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --S--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond. --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0219] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--NH--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --NH-- and X.sup.4 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --NH--, X.sup.4 is --CH.sub.2-
and X.sup.5 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --NH--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is
--CH.sub.2--. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0220] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--NH--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --NH--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --NH--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --NH--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0221] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--NH--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--NH--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0222] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--O--. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2
is --CH.sub.2--, X.sup.3 is --O-- and X.sup.4 is --CH.sub.2--. In
one or more embodiments. X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --O--, X.sup.4 is --CH.sub.2-- and X.sup.5
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --O--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is --CH.sub.2--.
In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0223] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --O--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --O--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --O--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --O--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0224] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --O--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --O--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0225] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--S--. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2
is --CH.sub.2--, X.sup.3 is --S-- and X.sup.4 is --CH.sub.2--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --S--, X.sup.4 is --CH.sub.2-- and X.sup.5
is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2-- and X.sup.6 is --CH.sub.2--.
In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0226] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0227] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0228] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--C(O)--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)-- and X.sup.4 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is
--CH.sub.2- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0229] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0230] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0231] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--S(O).sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O).sub.2- and
X.sup.4 is --CH.sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O).sub.2--,
X.sup.4 is --CH.sub.2-- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0232] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O).sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O).sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0233] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S(O).sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of
the above-embodiments, L is a bond. --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0234] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, and X.sup.3 is
--S(O)--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O)-- and X.sup.4 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O)--, X.sup.4 is
--CH.sub.2- and X.sup.5 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0235] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --S(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --CH--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --S(O)--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0236] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--S(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0237] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --NH--. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --NH-- and X.sup.5 is --CH.sub.2--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --NH--, X.sup.5
is --CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --NH--, X.sup.5 is
--CH.sub.2--, m is 0 and n is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--NH--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --NH--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--NH--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n
is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0238] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --NH--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --NH--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0239] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --NH--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --NH--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0240] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --O--. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --O-- and X.sup.5 is --CH.sub.2--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --O--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --O--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --O--, X.sup.5 is --CH.sub.2--,
m is 0 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --O--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --O--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --O--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --O--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0241] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --O--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --O--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --O--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --O--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0242] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --O--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --O--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --O--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0243] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --S--. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S-- and X.sup.5 is --CH.sub.2--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --S--, X.sup.5 is
--CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --S--, X.sup.5 is --CH.sub.2--,
m is 0 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --S--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --S--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0244] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --S--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --S--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --S--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0245] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --S--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0246] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --C(O)--. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)-- and X.sup.5 is --CH.sub.2--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, m is 0 and n is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.1 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--,
m is 0 and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0247] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --C(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0248] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0249] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --S(O).sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.1 is --CH.sub.2--, X.sup.4 is --S(O).sub.2-- and X.sup.1 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--S(O).sub.2--, X.sup.1 is --CH.sub.2-- and X.sup.6 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S(O).sub.2--, X.sup.5 is --CH.sub.2--, m is 0 and n is
0. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S(O).sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--S(O).sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --S(O).sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In
any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0250] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is --CH.sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --S(O).sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --S(O).sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0251] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --S(O).sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O).sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.4--, --C(O)(CR.sup.1R.sup.2).sup.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0252] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2-- and X.sup.4 is --S(O)--. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O)-- and X.sup.5 is --CH.sub.2--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5
is --CH.sub.2-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5
is --CH.sub.2--, m is 0 and n is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--S(O)--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and
n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0253] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --S(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0254] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --S(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0255] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --NH--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --NH-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --NH--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--NH--, m is 0 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --NH--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --NH--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --NH--, X.sup.6 is --CH.sub.2--, m is 0
and n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --NH--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0256] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --NH--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --NH--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --NH--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --NH--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --NH--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0257] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --NH--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --NH--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond. --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0258] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --O--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --O-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --O--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --O--,
m is 0 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --O--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --O--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --O--, X.sup.6 is --CH.sub.2--, m is 0 and
n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --O--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0259] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --O--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --O--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --O--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --O--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --O--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sup.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0260] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --O--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --O--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0261] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --S--. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S--, X.sup.6 is --CH.sub.2--
and m is 0. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S--,
m is 0 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S--, X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --S--, X.sup.6 is --CH.sub.2--, m is 0 and
n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0262] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S--, X.sup.6 is
--CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --S--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0263] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0264] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is --C(O)--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, m is 0 and n is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 0 and
n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0265] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.5
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --C(O)--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --C(O)--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0266] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0267] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2-- and X.sup.5 is
--S(O).sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2-- and X.sup.6 is
--CH.sub.2--. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--S(O).sub.2--, X.sup.6 is --CH.sub.2-- and m is 0. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--, m is 0 and n is
0. In one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --S(O).sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --S(O).sub.2--, X.sup.6 is --CH.sub.2--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S(O).sub.2--, X.sup.6 is --CH.sub.2--, m is 0 and n is
2. In one or more embodiments, X.sup.3 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S(O).sub.2--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3-, --S(O)--, --S(O)NR.sup.3--,
--C(O)CR.sup.1R.sup.2).sub.pO--, or
--C(O)CR.sup.1R.sup.2).sub.p--.
[0268] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--,
X.sup.6 is --CH.sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--, m
is 1 and n is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is
--S(O).sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any
of the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0269] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O).sub.2--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--S(O).sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--S(O).sub.2--, X.sup.6 is --CH.sub.2--, m is 1 and n is 2. In any
of the above-embodiments, L is a bond. --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0270] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.6 is --CH.sub.2-- and X.sup.5 is --S(O)--. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S(O)-- and X.sup.6 is --CH.sub.2--. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is
--CH.sub.2-- and m is 0. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S(O)--, m is 0 and n is 0. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is --CH.sub.2--, m is 0
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is --CH.sub.2--, m is 0
and n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S(O)--,
X.sup.6 is --CH.sub.2--, m is 0 and n is 2. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is
--CH.sub.2--, m is 0 and n is 2. In any of the above-embodiments, L
is a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0271] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6
is --CH.sub.2-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, m is 1 and n is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --S(O)--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5
is --S(O)--, X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --S(O)--,
X.sup.6 is --CH.sub.2--, m is 1 and n is 1. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0272] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6 is
--CH.sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --S(O)--, X.sup.6
is --CH.sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0273] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --NH--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --NH-- and m is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--NH--, m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --NH--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --NH--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --NH--, m is 0 and n is 2. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --NH--, m is 0 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --NH--, m is 0 and n is 2. In any
of the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(OX(R.sup.1R.sup.2).sub.p--.
[0274] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --NH-- and m is 1. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--NH--, m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --NH--, m is 1
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --NH--, m is 1 and n
is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0275] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --NH--, m is 1 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--NH--, m is 1 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--NH--, m is 1 and n is 2. In any of the above-embodiments, L is a
bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0276] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --O--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --O-- and m is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--,
m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --O--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --O--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --O--, m is 0 and n is 2. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --O--, m is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --O--, m is 0 and n is 2. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0277] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --O-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--,
m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--, m is 1
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.1 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--, m is 1 and n
is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0278] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --O--, m is 1 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--, m is 1
and n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --O--, m is 1 and
n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0279] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --C(O)--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --C(O)-- and m is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--C(O)--, m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --C(O)--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --C(O)--,
m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --C(O)--, m is 0 and n is 2. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --C(O)--, m is 0 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --C(O)--, m is 0 and n is 2. In any
of the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O)--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0280] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--. X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --C(O)-- and m is 1. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--C(O)--, m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --C(O)--, m is
1 and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --C(O)--, m is 1 and
n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0281] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --C(O)--, m is 1 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--C(O)--, m is 1 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--C(O)--, m is 1 and n is 2. In any of the above-embodiments, L is
a bond, --(CR.sup.1R.sup.2).sub.p--. --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0282] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --S(O).sub.2--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --S(O).sub.2--, and m is 0. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--. X.sup.5 is --CH.sub.2--,
X.sup.6 is --S(O).sub.2--, m is 0 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S(O).sub.2--, m is 0 and n is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --S(O).sub.2--, m is
0 and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --S(O).sub.2--, m is 0 and n is 2. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --S(O).sub.2--, m is 0 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --S(O).sub.2--, m is
0 and n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0283] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S(O).sub.2-- and m is 1. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S(O).sub.2--, m is 1 and n is 1. In one or more
embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.3 is --C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is
--CH.sub.2--, X.sup.6 is --S(O).sub.2--, m is 1 and n is 1. In one
or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --S(O).sub.2--, m is 1 and n is 1. In
any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0284] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --S(O).sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--C(O)--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6
is --S(O).sub.2--, m is 1 and n is 2. In one or more embodiments,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S(O).sub.2--, m is 1 and n is 2. In any of the
above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0285] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --S(O)--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --S(O)-- and m is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S(O)--, m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --S(O)--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --S(O)--,
m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --S(O)--, m is 0 and n is 2. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --S(O)--, m is 0 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --S(O)--, m is 0 and n is 2. In any
of the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0286] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S(O)-- and m is 1. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S(O)--, m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S(O)--, m is
1 and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S(O)--, m is 1 and
n is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0287] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --S(O)--, m is 1 and n is 2. In one or more embodiments, X.sup.1
is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S(O)--, m is 1 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S(O)--, m is 1 and n is 2. In any of the above-embodiments, L is
a bond, --(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--,
--S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0288] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2-- and
X.sup.6 is --S--. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --S-- and m is 0. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --(CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is
--S--, m is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5
is --CH.sub.2--, X.sup.6 is --S--, m is 0 and n is 1. In one or
more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6 is --S--, m
is 0 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --CH.sub.2--, X.sup.6 is --S--, m is 0 and n is 2. In
one or more embodiments, X.sup.1 is --CH.sub.2--, X.sup.2 is
--CH.sub.2--, X.sup.4 is --C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6
is --S--, m is 0 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.4 is --CH.sub.2--,
X.sup.5 is --C(O)--, X.sup.6 is --S--, m is 0 and n is 2. In any of
the above-embodiments, L is a bond, --(CR.sup.1R.sup.2).sub.p--,
--C(O)NR.sup.3--, --S(O).sub.2--, --S(O).sub.2NR.sup.3--, --S(O)--,
--S(O)NR.sup.3--, --C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0289] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--,
X.sup.6 is --S-- and m is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--,
X.sup.4 is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--,
m is 1 and n is 1. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--, m is 1
and n is 1. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--C(O)--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--, m is 1 and n
is 1. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0290] In one or more embodiments of the compounds of Formula IB,
X.sup.1 is --CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is
--CH.sub.2--, X.sup.4 is --CH.sub.2--, X.sup.5 is --C(O)--, X.sup.6
is --S--, m is 1 and n is 2. In one or more embodiments, X.sup.1 is
--CH.sub.2--, X.sup.2 is --CH.sub.2--, X.sup.3 is --C(O)--, X.sup.4
is --CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--, m is 1
and n is 2. In one or more embodiments, X.sup.1 is --CH.sub.2--,
X.sup.2 is --CH.sub.2--, X.sup.3 is --CH.sub.2--, X.sup.4 is
--CH.sub.2--, X.sup.5 is --CH.sub.2--, X.sup.6 is --S--, m is 1 and
n is 2. In any of the above-embodiments, L is a bond,
--(CR.sup.1R.sup.2).sub.p--, --C(O)NR.sup.3--, --S(O).sub.2--,
--S(O).sub.2NR.sup.3--, --S(O)--, --S(O)NR.sup.3--,
--C(O)(CR.sup.1R.sup.2).sub.pO--, or
--C(O)(CR.sup.1R.sup.2).sub.p--.
[0291] In one or more embodiments of the compounds of Formula IB,
the compound is of the formula IB-1, IB-2, IB-3, IB-4, IB-5, IB-6,
IB-7, or IB-8:
##STR00006##
[0292] In one or more embodiments, a compound of Formula I can be:
[0293]
(R)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-1); [0294]
(S)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-2); [0295]
(R)--N-hydroxy-1'-isopropyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidi-
ne]-5-carboxamide (I-3); [0296]
(S)--N-hydroxy-1'-isopropyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidi-
ne]-5-carboxamide (I-4); [0297]
(R)-1'-ethyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-
-carboxamide (I-5); [0298]
(S)-1'-ethyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-
-carboxamide (I-6); [0299]
(R)--N-hydroxy-1'-isobutyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidin-
e]-5-carboxamide (I-7). [0300]
(S)--N-hydroxy-1'-isobutyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidin-
e]-5-carboxamide (I-8); [0301]
(R)--N-hydroxy-1'-(2-methylbenzyl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-py-
rrolidine]-5-carboxamide (I-9); [0302]
(S)--N-hydroxy-1'-(2-methylbenzyl)-2'-oxo-1,3-dihydrospiro[indene-2,3'-py-
rrolidine]-5-carboxamide (I-10); [0303]
(R)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]--
5-carboxamide (I-11); [0304]
(S)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]--
5-carboxamide (I-12); [0305]
(R)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-13); [0306]
(S)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-14); [0307]
(R)-1'-(4-fluorophenyl)-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyr-
rolidine]-5-carboxamide (I-15); [0308]
(S)-1'-(4-fluorophenyl)-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyr-
rolidine]-5-carboxamide (I-16); [0309]
(R)--N-hydroxy-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-17); [0310]
(S)--N-hydroxy-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide [0311]
(R)--N-hydroxy-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-19); [0312]
(S)--N-hydroxy-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-20); [0313]
(R)--N-hydroxy-2'-oxo-1'-(pyridin-4-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-21), [0314]
(S)--N-hydroxy-2'-oxo-1'-(pyridin-4-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-22); [0315]
(R)--N-hydroxy-2'-oxo-1'-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3-
'-pyrrolidine]-5-carboxamide (I-23); [0316]
(R)--N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carb-
oxamide (I-24); [0317]
(S)--N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carb-
oxamide (I-25); [0318]
(R)-1'-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carbo-
xamide (I-26); [0319]
(S)-1'-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carbo-
xamide (I-27); [0320]
(R)-1'-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carbo-
xamide (I-28); [0321]
(S)-1'-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carbo-
xamide (I-29); [0322]
(R)-1'-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carb-
oxamide (I-30); [0323]
(S)-1'-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carb-
oxamide (I-31); [0324]
(R)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide (I-32); [0325]
(S)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide (I-33); [0326]
(R)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-
-carboxamide (I-34); [0327]
(S)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-
-carboxamide (I-35); [0328]
(R)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide (I-36); or [0329]
(S)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide (I-37).
[0330] In one or more embodiments, a compounds of Formula I can be:
[0331]
N-hydroxy-1'-methyl-5'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-ca-
rboxamide (I-38); [0332]
N-hydroxy-1'-methyl-6'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-car-
boxamide (I-39); [0333]
N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-5-car-
boxamide (I-40); [0334]
N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxamid-
e (I-41); [0335]
N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,4'-piperidine]-5-carboxamid-
e (I-42); [0336]
N-hydroxy-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]-6-carboxamide
(I-43); or [0337]
N-hydroxy-1'-methyl-3H-spiro[benzofuran-2,4'-piperidine]-6-carboxamide
(I-44).
[0338] In some embodiments of the invention, the compounds of
Formula I are enantiomers. In some embodiments the compounds are
the (S)-enantiomer. In other embodiments the compounds are the
(R)-enantiomer. In yet other embodiments, the compounds of Formula
I may be (+) or (-) enantiomers. As used herein, a chemical
structure that is labelled as "R/S" indicates that the structure
represents one enantiomer, the stereochemistry of which is not
defined.
[0339] It should be understood that all isomeric forms are included
within the present invention, including mixtures thereof. If the
compound contains a double bond, the substituent may be in the E or
Z configuration. If the compound contains a disubstituted
cycloalkyl, the cycloalkyl substituent may have a cis- or
trans-configuration. All tautomeric forms are also intended to be
included.
Methods of Synthesizing the Disclosed Compounds
[0340] The compounds of the present invention may be made by a
variety of methods, including standard chemistry. Suitable
synthetic routes are depicted in the schemes given below.
[0341] The compounds of Formula I may be prepared by methods known
in the art of organic synthesis as set forth in part by the
following synthetic schemes and examples. In the schemes described
below, it is well understood that protecting groups for sensitive
or reactive groups are employed where necessary in accordance with
general principles or chemistry. Protecting groups are manipulated
according to standard methods of organic synthesis (T. W. Greene
and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third
edition, Wiley, New York 1999). These groups are removed at a
convenient stage of the compound synthesis using methods that are
readily apparent to those skilled in the art. The selection
processes, as well as the reaction conditions and order of their
execution, shall be consistent with the preparation of compounds of
Formula I.
[0342] Those skilled in the art will recognize if a stereocenter
exists in the compounds of Formula I. Accordingly, the present
invention includes both possible stereoisomers (unless specified in
the synthesis) and includes not only racemic compounds but the
individual enantiomers and/or diastereomers as well. When a
compound is desired as a single enantiomer or diastereomer, it may
be obtained by stereospecific synthesis or by resolution of the
final product or any convenient intermediate. Resolution of the
final product, an intermediate, or a starting material may be
affected by any suitable method known in the art. See, for example,
"Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen,
and L. N. Mander (Wiley-Interscience, 1994).
Preparation of Compounds
[0343] The compounds described herein may be made from commercially
available starting materials or synthesized using known organic,
inorganic, and/or enzymatic processes.
[0344] The compounds of the present invention can be prepared in a
number of ways well known to those skilled in the art of organic
synthesis. By way of example, compounds of the Formula I (e.g.,
Formula IA-9 and IA-10) can be synthesized using the methods
described below, together with synthetic methods known in the art
of synthetic organic chemistry, or variations thereon as
appreciated by those skilled in the art. These methods include but
are not limited to those methods described below.
##STR00007## ##STR00008##
wherein L and R are defined as in Formula (I).
[0345] The general way of preparing target molecules of Formula
(IA-9) by using intermediates 1a, 1b, 1c, 1d, 1e, 1f, 1g, and 1h is
outlined in Scheme 1. Carbonylation of
5-bromo-2,3-dihydro-1H-inden-1-one (1a) in the presence of a metal
catalyst, e.g.,
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(Pd(dppf)Cl.sub.2), carbon monoxide, and a base, e.g.,
triethylamine (Et.sub.3N), provides ester 1b. Deprotonation of 1b
using a strong base, e.g., sodium hydride (NaH), in the presence of
dimethyl carbonate affords Intermediate 1c, which can be alkylated
by treatment with a halo-nitrile in the presence of a base to
provide Intermediates 1d. Reduction, for example, with hydrogen gas
in the presence of platinum (IV) oxide (PtO.sub.2), acetic acid,
and methanol, can provide amino-alcohol Intermediates 1e.
Spiro-lactams 1f can be obtained by treatment of 1e with ammonia
(NH.sub.3) in methanol. Dehydroxylation of 1f by conversion to the
silyl ether can be accomplished by treatment with triethylsilane
and TFA to provide Intermediates 1g. Addition of the R-L moiety can
be achieved via standard methods of alkylation or arylation. For
example, alkylation of 1g with an alkyl halide in the presence of a
base, e.g., sodium hydride, can provide compounds of Intermediates
1h. Alternatively, arylation of 1g with an aryl boronic acid in the
presence of a metal catalyst, e.g., copper (II) acetate
(Cu(OAc).sub.2), and a base, e.g., Et.sub.3N, can also provide
compounds of Intermediates 1h. Treatment of 1h with hydroxylamine
and a base, e.g., sodium hydroxide, provides compounds of Formula
(IA-9).
##STR00009##
wherein L and R are defined as in Formula (I).
[0346] The general way of preparing target molecules of Formula
(IA-10) by using intermediates 1g, 1i, 1j, and 1k is outlined in
Scheme 2. Spiro-amines 1j can be obtained via reduction of
thiolactam 1i by treatment of 1g with
2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane
(Lawesson reagent), followed by sodium borohydride (NaBH.sub.4) in
the presence of Nickel (II) chloride hexahydrate
(NiCl.sub.2.6H.sub.2O). Addition of the R-L moiety can be achieved
via standard methods of alkylation, arylation, acylation, urea
formation, or sulfonation. Treatment of 1k with hydroxylamine and a
base, e.g., sodium hydroxide, provides compounds of Formula
(IA-10).
Methods of Using the Disclosed Compounds
[0347] Another aspect of the invention relates to a method of
treating a disease associated with HDAC6 modulation in a subject in
need thereof. The method involves administering to a patient in
need of treatment for diseases or disorders associated with HDAC6
modulation an effective amount of a compound of Formula I. In an
embodiment, the disease can be, but is not limited to, cancer,
neurodegenerative disease, neurodevelopmental disease, inflammatory
or autoimmune disease, infection, metabolic disease, hematologic
disease, transplant rejection, or cardiovascular disease.
[0348] Another aspect of the invention is directed to a method of
inhibiting HDAC6. The method involves administering to a patient in
need thereof an effective amount of Formula I.
[0349] The present invention relates to compositions capable of
modulating the activity of (e.g., inhibiting) HDACs, and in
particular HDAC6. The present invention also relates to the
therapeutic use of such compounds.
[0350] One therapeutic use of the compounds of the present
invention is to treat proliferative diseases or disorders such as
cancer. Cancer can be understood as abnormal or unregulated cell
growth within a patient and can include but is not limited to lung
cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic
cancer, hepatocellular cancer, renal cancer and leukemias such as
acute myeloid leukemia and acute lymphoblastic leukemia. Additional
cancer types include T-cell lymphoma (e.g., cutaneous T-cell
lymphoma, peripheral T-cell lymphoma), Hodgkin lymphoma, melanoma
and multiple myeloma. In other embodiments, treating proliferative
diseases or disorders can include any cancer where there is
evidence of an increase in Treg/effector T cell ratio or in an
absolute Treg number, either in the periphery or in the tumor
microenvironment or tertiary lymphoid structures, or increased
expression of T cell tolerance-related genes. Such proliferative
diseases or disorders can include but are not limited to: any Kras
mutant carrying tumor (Zdanov et al., Mutant KRAS conversion of
conventional T cells into regulatory T cells. Cancer Immunol. Res.
Feb. 15, 2016, DOI: 10.1158/2326-6066.CIR-15-0241); renal cell
carcinoma; lung carcinoma; cervical cancer, prostate cancer;
ovarian cancer; head and neck cancer, lymphoma; colorectal cancer,
non-small cell lung carcinoma; breast cancers (Gobert, M. et al.,
(2009) Cancer Res. 69, 2000-2009); and bladder cancer.
[0351] One therapeutic use of the compounds of the present
disclosure is to treat neurological diseases or disorders or
neurodegeneration. Neurological disorders are understood as
disorders of the nervous system (e.g., the brain and spinal cord).
Neurological disorders or neurodegenerative diseases can include
but are not limited to epilepsy, attention deficit disorder (ADD),
Alzheimer's disease, Parkinson's Disease, Huntington's Disease,
amyotrophic lateral sclerosis, spinal muscular atrophy, essential
tremor, central nervous system trauma caused by tissue injury,
oxidative stress-induced neuronal or axomal degeneration, and
multiple sclerosis.
[0352] Another therapeutic use of the compounds of the present
disclosure is to treat neurodevelopmental disorders.
Neurodevelopmental disorders can include, but are not limited to,
Rett syndrome, intellectual disability, intellectual and
developmental disability, autism spectrum disorder, fetal alcohol
syndrome, developmental coordination disorder, stereotypic movement
disorder, Tourette syndrome, cerebral palsy, fragile X syndrome,
attention deficit hyperactivity disorder, and Mendelsohnn's
syndrome.
[0353] Another therapeutic use of the compounds of the present
invention is also to treat inflammatory diseases or disorders.
Inflammation can be understood as a host's response to an initial
injury or infection. Symptoms of inflammation can include but are
not limited to redness, swelling, pain, heat and loss of function.
Inflammation may be caused by the upregulation of pro-inflammatory
cytokines such as IL-1.beta., and increased expression of the FOXP3
transcription factor. In some embodiments, the inflammatory
diseases include fibrosis or fibrotic diseases. Types of fibrotic
diseases include but are not limited to lung fibrosis or pulmonary
fibrosis, Liver fibrosis; Heart fibrosis; Mediastinal fibrosis;
Retroperitoneal cavity fibrosis; Bone marrow fibrosis; Skin
fibrosis, and Scleroderma or systemic sclerosis.
[0354] Another therapeutic use of the compounds of the present
invention is also to treat autoimmune diseases or disorders.
Autoimmune disorders are understood as disorders wherein a host's
own immune system responds to tissues and substances occurring
naturally in the host's body. Autoimmune diseases can include but
are not limited to rheumatoid arthritis, Crohn's disease, type-1
diabetes, systemic juvenile idiopathic arthritis; inflammatory
bowel disease; allograft transplantation; eczema, psoriasis,
idiopathic thrombocytopenic purpra, autoimmune thrombocytopenia,
acquired immune thrombocytopenia, autoimmune neutropenia,
autoimmune hemolyitic anemia, parvovirus B19-associated red cell
aplasia, acquired antifactor VIII autoimmunity, acquired von
Willebrand disease, monoclonal gammopathy, aplastic anemia, pure
red cell aplasia, Diamond-Blackfan anemia, hemolytic disease of the
newborn, immune mediated-refractoriness to platelet transfusion,
hemolytic uremic syndrome, Evan's syndrome, Guillain-Barre
syndrome, chronic demyelinating polyradiculoneuropathy,
paraproteinemic IgM demyelinating polyneuropathy, Lamber-Eaton
myasthenic syndrome, myasthenia gravis, multifocal motor
neuropathy, stiff man syndrome, paraneoplastic encephalomyelitis,
sensory neuropathy with anti-Hu antibodies, myelitis, autoimmune
diabetic neuropathy, acute idiopathic neuropathy, toxic epidermal
necrolysis, gangrene, granuloma, pemphigus vulgaris, bullous
pemphigoid, vitiligo, scleroderma, atomic dermatitis, systemic and
diffuse sclerosis, primary biliary cirrhosis, Celiac disease,
dermatitis herpetiformis, cryptogenic cirrhosis, reactive
arthritis, Hashimoto's thryroditis, Wegner's granulomoatosis,
micropolyarterits, Churg-Strauss syndrome Type I and Type II
autoimmune polyglandular syndromes, linear IgA disease,
epidermolysis bullosa acquisita, erythema nodosa, pemphigoid
gestationis, cicatricial pemphigoid, mixed essential
cryoglobulinemia, chronic bullous disease of childhood,
Goodpasture's syndrome, sclerosis cholangitis, ankylosing
spondylitis, Bechet's syndrome temporal arteritis, Takayasu's
arteritis, autoimmune urticaria, and Kawasaki's disease.
[0355] In some embodiments, the cancer to be treated is melanoma,
cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin
lymphoma, multiple myeloma, leukemia, lung, ovarian, breast,
prostate, pancreatic, hepatocellular or renal cancer. In some
embodiments, the cancer to be treated is cutaneous T-cell lymphoma,
peripheral T-cell lymphoma, multiple myeloma, lymphoma, leukemia,
lung, ovarian, breast, prostate, pancreatic, hepatocellular or
renal cancer. In other embodiments, the neurodegenerative disease
to be treated is Alzheimer's Disease, Huntington's Disease,
Parkinson's Disease, Amyotrophic Lateral Sclerosis, or spinal
muscular atrophy. In other embodiments, the neurodevelopmental
disorder to be treated is Rett syndrome. In yet other embodiments,
the inflammatory or autoimmune disease to be treated is rheumatoid
arthritis, spondylitis arthritis, psoriatic arthritis, psoriasis,
multiple sclerosis, systemic lupus erythematosus, inflammatory
bowel diseases, graft versus host disease, transplant rejection or
fibrotic disease.
[0356] Another therapeutic use of the compounds of the present
invention is also to treat and/or prevent allergy and unwanted
immune responses associated with allergy. A non-limiting list of
allergies and related conditions includes, pollen allergy (e.g.
Japanese Cedar Pollen), mold allergy, food allergies (including,
but not limited to peanut, tree nut, milk, soy, gluten, and egg
allergies), animal allergies (e.g. allergies to dogs, cats,
rabbits), dust mite allergy, atopic dermatitis, allergic rhinitis,
allergic otitis, allergic asthma, dry eye, ocular allergy, allergic
urticaria, contact dermatitis, anaphalaxis, eosinophilic
esophagitis.
[0357] Another therapeutic use of the compounds of the present
invention is also to treat infectious diseases or disorders.
Infections or infectious diseases are caused by the invasion of a
foreign pathogen. The infection may be caused by, for instance, a
bacteria, a fungus, or virus. Bacterial infections include, but are
not limited to streptococcus infections, mycobacterial infections,
bacillus infections, Salmonella infections, Vibrio infections,
spirochete infections, and Neisseria infections. Viral infections
include, but are not limited to herpes virus infections, hepatitis
virus infections, west nile virus infections, flavivrus infections,
influenza virus infections, rhinovirus infections, papillomavirus
infections, paromyxovirus infections, parainfluenza virus
infections, and retrovirus infections. In particular embodiments,
the compounds of the present invention are useful for treating
infections which result in an inflammatory cytokine burst.
Nonlimiting examples of such infections include Ebola and the viral
hemorghagic fever-causing viruses, and Malaria.
[0358] Yet another therapeutic use of the compounds of the present
invention is also to treat metabolic diseases or disorders.
Metabolic diseases can be characterized as abnormalities in the way
that a subject stores energy. Metabolic disorders can include but
are not limited to metabolic syndrome, diabetes, obesity, high
blood pressure, non-alcoholic fatty liver disease and heart
failure.
[0359] Yet another therapeutic use of the compounds of the present
invention is also to treat hematologic disorders. Hematologic
diseases primarily affect the blood. Hematologic disorders can
include but are not limited to anemia, multiple myeloma, lymphoma,
and leukemia.
[0360] Yet another therapeutic use of the compounds of the present
invention is also to prevent and/or treat transplant rejection.
Tissues that are transplanted include (but are not limited to)
whole organs such as kidney, liver, heart, lung, organ components
such as skin grafts and the cornea of the eye; and cell suspensions
such as bone marrow cells and cultures of cells selected and
expanded from bone marrow or circulating blood, and whole blood
transfusions.
[0361] Yet another therapeutic use of the compounds of the present
invention is also to treat cardiovascular diseases or disorders.
Cardiovascular diseases affect the heart and blood vessels of a
patient. Exemplary conditions include but are not limited to
cardiovascular stress, pressure overload, chronic ischemia,
infarction-reperfusion injury, hypertension, Brain infarct after
cerebral artery occlusion, atherosclerosis, peripheral artery
disease, cardiac hypertrophy, cardiac arrhythmias, stroke, and
heart failure.
[0362] Another therapeutic use of the compounds of the present
invention is for purging the reservoir of latently infected memory
CD4+ T cells in HIV+ patients (Matalon, et al., Mol Med. 2011;
17(5-6); 466-472), which is hereby incorporated by reference in its
entirety.
[0363] The disclosed compound can be administered in effective
amounts to treat or prevent a disorder and/or prevent the
development thereof in subjects.
[0364] Another aspect of the present disclosure relates to a
compound of Formula I, or a pharmaceutically acceptable salt,
hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for
use in treating or preventing a disease associated with HDAC6
modulation. In some embodiments, the disease is cancer,
neurodegenerative disease, neurodevelopmental disorder,
inflammatory or autoimmune disease, infection, metabolic disease,
hematologic disease, transplant rejection or cardiovascular
disease. In some embodiments, the compound inhibits a histone
deacetylase. In another embodiment, the compound inhibits a
zinc-dependent histone deacetylase. In another embodiment, the
compound inhibits the HDAC6 isozyme zinc-dependent histone
deacetylase.
[0365] In another aspect, the present disclosure relates to the use
of a compound of Formula (I), or a pharmaceutically acceptable
salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof,
in the manufacture of a medicament for treating or preventing a
disease associated with HDAC6 modulation. In some embodiments, the
disease is cancer, neurodegenerative disease, neurodevelopmental
disorder, inflammatory or autoimmune disease, infection, metabolic
disease, hematologic disease, transplant rejection, or
cardiovascular disease. In some embodiments, the compound inhibits
a histone deacetylase. In another embodiment, the compound inhibits
a zinc-dependent histone deacetylase. In another embodiment, the
compound inhibits the HDAC6 isozyme zinc-dependent histone
deacetylase.
[0366] In some embodiments, the cancer is melanoma, cutaneous
T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin lymphoma,
multiple myeloma, leukemia, lung, ovarian, breast, prostate,
pancreatic, hepatocellular or renal cancer. In some embodiments,
the cancer is cutaneous T-cell lymphoma, peripheral T-cell
lymphoma, multiple myeloma, lymphoma, leukemia, lung, ovarian,
breast, prostate, pancreatic, hepatocellular or renal cancer. In
other embodiments, the neurodegenerative disease is Alzheimer's
Disease, Huntington's Disease, Parkinson's Disease, Amyotrophic
Lateral Sclerosis, or spinal muscular atrophy. In other
embodiments, the neurodevelopmental disorder is Rett syndrome. In
yet other embodiments, the inflammatory or autoimmune disease is
rheumatoid arthritis, spondylitis arthritis, psoriatic arthritis,
psoriasis, multiple sclerosis, systemic lupus erythematosus,
inflammatory bowel diseases, graft versus host disease, transplant
rejection or fibrotic disease.
[0367] Administration of the disclosed compounds can be
accomplished via any mode of administration for therapeutic agents.
These modes include systemic or local administration such as oral,
nasal, parenteral, transdermal, subcutaneous, vaginal, buccal,
rectal or topical administration modes.
[0368] Depending on the intended mode of administration, the
disclosed compositions can be in solid, semi-solid or liquid dosage
form, such as, for example, injectables, tablets, suppositories,
pills, time-release capsules, elixirs, tinctures, emulsions,
syrups, powders, liquids, suspensions, or the like, sometimes in
unit dosages and consistent with conventional pharmaceutical
practices. Likewise, they can also be administered in intravenous
(both bolus and infusion), intraperitoneal, subcutaneous or
intramuscular form, and all using forms well known to those skilled
in the pharmaceutical arts.
[0369] Illustrative pharmaceutical compositions are tablets and
gelatin capsules comprising a compound of the disclosure and a
pharmaceutically acceptable carrier, such as a) a diluent, e.g.,
purified water, triglyceride oils, such as hydrogenated or
partially hydrogenated vegetable oil, or mixtures thereof, corn
oil, olive oil, sunflower oil, safflower oil, fish oils, such as
EPA or DHA, or their esters or triglycerides or mixtures thereof,
omega-3 fatty acids or derivatives thereof, lactose, dextrose,
sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose
and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid,
its magnesium or calcium salt, sodium oleate, sodium stearate,
magnesium stearate, sodium benzoate, sodium acetate, sodium
chloride and/or polyethylene glycol; for tablets also, c) a binder,
e.g., magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose,
magnesium carbonate, natural sugars such as glucose or
beta-lactose, corn sweeteners, natural and synthetic gums such as
acacia, tragacanth or sodium alginate, waxes and/or
polyvinylpyrrolidone, if desired; d) a disintegrant, e.g.,
starches, agar, methyl cellulose, bentonite, xanthan gum, algiic
acid or its sodium salt, or effervescent mixtures; e) absorbent,
colorant, flavorant and sweetener, f) an emulsifier or dispersing
agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,
labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12,
captex 355, gelucire, vitamin E TGPS or other acceptable
emulsifier; and/or g) an agent that enhances absorption of the
compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400,
PEG200.
[0370] Liquid, particularly injectable, compositions can, for
example, be prepared by dissolution, dispersion, etc. For example,
the disclosed compound is dissolved in or mixed with a
pharmaceutically acceptable solvent such as, for example, water,
saline, aqueous dextrose, glycerol, ethanol, and the like, to
thereby form an injectable isotonic solution or suspension.
Proteins such as albumin, chylomicron particles, or serum proteins
can be used to solubilize the disclosed compounds.
[0371] The disclosed compounds can be also formulated as a
suppository that can be prepared from fatty emulsions or
suspensions; using polyalkylene glycols such as propylene glycol,
as the carrier.
[0372] The disclosed compounds can also be administered in the form
of liposome delivery systems, such as small unilamellar vesicles,
large unilamellar vesicles and multilamellar vesicles. Liposomes
can be formed from a variety of phospholipids, containing
cholesterol, stearylamine or phosphatidylcholines. In some
embodiments, a film of lipid components is hydrated with an aqueous
solution of drug to a form lipid layer encapsulating the drug, as
described in U.S. Pat. No. 5,262,564.
[0373] Disclosed compounds can also be delivered by the use of
monoclonal antibodies as individual carriers to which the disclosed
compounds are coupled. The disclosed compounds can also be coupled
with soluble polymers as targetable drug carriers. Such polymers
can include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the disclosed
compounds can be coupled to a class of biodegradable polymers
useful in achieving controlled release of a drug, for example,
polylactic acid, polyepsilon caprolactone, polyhydroxy butyric
acid, polyorthoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and cross-linked or amphipathic block copolymers
of hydrogels. In one embodiment, disclosed compounds are not
covalently bound to a polymer, e.g., a polycarboxylic acid polymer,
or a polyacrylate.
[0374] Parental injectable administration is generally used for
subcutaneous, intramuscular or intravenous injections and
infusions. Injectables can be prepared in conventional forms,
either as liquid solutions or suspensions or solid forms suitable
for dissolving in liquid prior to injection.
[0375] Another aspect of the invention relates to a pharmaceutical
composition comprising a compound of Formula I and a
pharmaceutically acceptable carrier. The pharmaceutically
acceptable carrier can further include an excipient, diluent, or
surfactant.
[0376] Compositions can be prepared according to conventional
mixing, granulating or coating methods, respectively, and the
present pharmaceutical compositions can contain from about 0.1% to
about 99%, from about 5% to about 90%, or from about 1% to about
20% of the disclosed compound by weight or volume.
[0377] The dosage regimen utilizing the disclosed compound is
selected in accordance with a variety of factors including type,
species, age, weight, sex and medical condition of the patient; the
severity of the condition to be treated; the route of
administration; the renal or hepatic function of the patient; and
the particular disclosed compound employed. A physician or
veterinarian of ordinary skill in the art can readily determine and
prescribe the effective amount of the drug required to prevent,
counter or arrest the progress of the condition.
[0378] Effective dosage amounts of the disclosed compounds, when
used for the indicated effects, range from about 0.5 mg to about
5000 mg of the disclosed compound as needed to treat the condition.
Compositions for in vivo or in vitro use can contain about 0.5, 5,
20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or
5000 mg of the disclosed compound, or, in a range of from one
amount to another amount in the list of doses. In one embodiment,
the compositions are in the form of a tablet that can be
scored.
[0379] Without wishing to be bound by any particular theory, the
compounds of the present invention can inhibit HDACs such as HDAC6
by interacting with the zinc (Zn.sup.2+) ion in the protein's
active site via the hydroxamic acid group bound to the aromatic
ring of the compound. The binding can prevent the zinc ion from
interacting with its natural substrates, thus inhibiting the
enzyme.
EXAMPLES
[0380] The disclosure is further illustrated by the following
examples and synthesis examples, which are not to be construed as
limiting this disclosure in scope or spirit to the specific
procedures herein described. It is to be understood that the
examples are provided to illustrate certain embodiments and that no
limitation to the scope of the disclosure is intended thereby. It
is to be further understood that resort may be had to various other
embodiments, modifications, and equivalents thereof which may
suggest themselves to those skilled in the art without departing
from the spirit of the present disclosure and/or scope of the
appended claims.
[0381] The present invention includes a number of unique features
and advantages compared with other inhibitors of HDAC enzymes, in
particular HDAC6. For instance, the present invention features a
unique class of small molecule therapeutic agents of Formula I.
[0382] Definitions used in the following examples and elsewhere
herein are:
TABLE-US-00001 AcOH Acetic Acid CH.sub.2Cl.sub.2 Methylene
chloride, Dichloromethane CH.sub.3CN Acetonitrile CH.sub.3I
Iodomethane CO (g) Carbon monoxide (gas) CO.sub.2 Carbon dioxide
Cs.sub.2CO.sub.3 Cesium carbonate Cu(OAc).sub.2 Copper (II) acetate
DMA Dimethylacetamide DMF N,N-Dimethylformamide DMSO
Dimethylsulfoxide Et.sub.3N Triethylamine EtOAc Ethyl acetate EtOH
Ethanol h hours H.sub.2 (g) Hydrogen (gas) H.sub.2O Water HCl
Hydrochloric acid MeOH Methanol min minutes Na.sub.2SO.sub.4 Sodium
sulfate NaBH.sub.3CN Sodium cyanoborohydride NaBH.sub.4 Sodium
borohydride NaH Sodium hydride NaHCO.sub.3 Sodium bicarbonate NaOH
Sodium hydroxide NH.sub.2OH Hydroxylamine NH.sub.3 Ammonia
NH.sub.4HCO.sub.3 Ammonium bicarbonate NiCl.sub.2.cndot.6H.sub.2O
Nickel (II) chloride hexahydrate NMM 4-Methylmorpholine O.sub.2 (g)
Oxygen (gas) Pd(dppf)Cl.sub.2 [1,1'-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PtO.sub.2
Platinum (IV) oxide RuPhos
2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl RuPhos Pd G2 2nd
Generation RuPhos Precatalyst, Chloro(2-
dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-
biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)
Example 1--Preparation of
(R)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide and
(S)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-1 and I-2)
##STR00010##
[0383] Step-1: Methyl 1-oxo-2,3-dihydro-1H-indene-5-carboxylate
[0384] Into a 1-L round-bottom flask was placed a solution of
5-bromo-2,3-dihydro-1H-inden-1-one (30 g, 142 mmol, 1 equiv) in
MeOH (450 mL), Pd(dppf)Cl.sub.2 (15.6 g, 21.32 mmol, 0.15 equiv)
and Et.sub.3N (57.5 g, 568 mmol, 4 equiv). CO (g) was introduced to
the flask. The reaction mixture was stirred for 24 h at 100.degree.
C. in an oil bath, then cooled to room temperature. The solids were
filtered and the filtrate was concentrated under vacuum. The
residue was purified by normal phase chromatography on silica gel
using EtOAc/petroleum ether (1:10). The collected fractions were
concentrated under vacuum to afford 18 g (67% yield) of the title
compound as a yellow solid. MS: (ES, m/z): 191 [M+H].sup.+.
Step-2: Dimethyl 1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate
[0385] Into a 250-mL round-bottom flask was placed a solution of
methyl 1-oxo-2,3-dihydro-1H-indene-5-carboxylate (10 g, 52.58 mmol,
1 equiv) in dimethyl carbonate (100 mL). NaH (60% in mineral oil,
4.2 g, 175 mmol, 2 equiv) was added. The resulting solution was
stirred for 2 h at 80.degree. C. in an oil bath. The reaction
mixture was cooled to room temperature and poured into ice water
(50 mL). The solids were filtered and the filtrate was extracted
with EtOAc (3.times.100 mL). The combined organic layers were dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
vacuum. The residue purified by normal phase chromatography on
silica gel using EtOAc/petroleum ether (1:10). The collected
fractions were concentrated under vacuum to afford 5.8 g (44%
yield) of the title compound as a yellow solid. MS: (ES, m/z): 249
[M+H].sup.+.
Step-3: Dimethyl
2-(cyanomethyl)-1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate
[0386] Into a 1-L round-bottom flask was placed a solution of
dimethyl 1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate (11.8 g,
47.54 mmol, 1 equiv) in THF (500 mL), Et.sub.3N (24.0 g, 237.68
mmol, 5 equiv) and 2-bromoacetonitrile (17.1 g, 142.61 mmol, 3
equiv). The reaction was stirred for 16 h at 25.degree. C. The
solids were filtered out and the filtrate was concentrated under
vacuum. The residue was purified by normal phase chromatography on
silica gel using EtOAc/petroleum ether (1:5). The collected
fractions were concentrated under vacuum to afford 3.1 g (23%
yield) of the title compound as a yellow solid. MS: (ES, m/z): 288
[M+H].sup.+.
Step-4: Dimethyl
2-(2-aminoethyl)-1-hydroxy-2,3-dihydro-1H-indene-2,5-dicarboxylate
[0387] Into a 500-mL round-bottom flask was placed dimethyl
2-(cyanomethyl)-1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate (3 g,
10.44 mmol, 1 equiv), MeOH (100 mL), PtO.sub.2 (3 g) and AcOH (30
mL). H.sub.2 (g) was introduced into the flask. The resulting
solution was stirred for 4 h at 25.degree. C. The reaction mixture
was cooled to room temperature and the solids were filtered out.
The filtrate was concentrated under vacuum to afford 2 g (crude) of
the title compound as a yellow oil. MS: (ES, m/z): 294
[M+H].sup.+.
Step-5: Methyl
1-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0388] Into a 250-mL round-bottom flask was placed dimethyl
2-(2-aminoethyl)-1-hydroxy-2,3-dihydro-H-indene-2,5-dicarboxylate
(2 g, 6.82 mmol, 1 equiv) and NH.sub.3 (7 M in MeOH, 30 mL). The
reaction was stirred for 1 h at 25.degree. C. The resulting mixture
was concentrated under vacuum. The crude product was
re-crystallized from CH.sub.2Cl.sub.2 to afford 500 mg (28% yield)
of the title compound as a white solid. MS: (ES, m/z): 262
[M+H].sup.+.
Step-6: Methyl
2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0389] Into a 100-mL round-bottom flask was placed a solution of
methyl
1-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
(900 mg, 3.44 mmol, 1 equiv) in TFA (10 mL) and triethylsilane (10
mL). The reaction was stirred for 12 h at 80.degree. C. in an oil
bath. The reaction mixture was cooled to room temperature and
concentrated under vacuum. The residue was purified by normal phase
chromatography on silica gel using an EtOAc/petroleum ether
gradient. The collected fractions were concentrated under vacuum to
afford 400 mg of the title compound as a white solid. MS: (ES,
m/z): 246 [M+H].sup.+.
Step-7: Chiral separation of methyl
(R)-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
and methyl
(S)-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0390] Racemic methyl
2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate was
purified by Chiral-Prep-HPLC with the following conditions: Column:
Phenomenex Lux.RTM. Cellulose-4 AXIA.TM. Packed, 250.times.21.2 mm,
5 .mu.m; Mobile Phase A: hexanes, Mobile Phase B: EtOH; Gradient:
hold 30% B for 23 min, Detector: UV 254 nm and 220 nm. The first
eluting isomer (Rt 2.46 min) was collected and concentrated under
vacuum to afford 210 mg (25% yield) of a white solid which was
assigned as the R isomer of methyl
2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate. MS:
(ES, m/z): 246 [M+H].sup.+. The second eluting isomer (Rt 3.21 min)
was collected and concentrated under vacuum to afford 200 mg (24%
yield) of a white solid which was assigned as the S isomer of
methyl
2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate. MS:
(ES, m/z): 246 [M+H].sup.+.
Step-8: Methyl
(R)-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxyl-
ate
[0391] Into an 8-mL vial was placed a solution of the first eluted
isomer from Step 7, which was assigned as methyl
(R)-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
as described above, (50 mg, 0.20 mmol, 1 equiv) in DMF (3 mL). The
solution was cooled to 0.degree. C. NaH (60% in mineral oil, 16.3
mg, 0.41 mmol, 2 equiv), was added in portions at 0.degree. C. The
resulting solution was stirred for 30 min at 0.degree. C. CH.sub.3I
(57.8 mg, 0.41 mmol, 2 equiv) was added and the resulting solution
was stirred for 2 h at 25.degree. C. The reaction mixture was
poured into 10 mL of water and extracted with EtOAc (2.times.20
mL). The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum to afford 30 mg (51% yield)
of the title compound as a yellow solid. MS: (ES, m/z): 260
[M+H].sup.+.
Step-9:
(R)--N-Hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrro-
lidine]-5-carboxamide
[0392] Into an 8-mL vial was placed methyl
(R)-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxyl-
ate (30 mg, 0.12 mmol, 1 equiv), THF/MeOH (4:1, 2.5 mL), NH.sub.2OH
(50% in water, 917 mg, 27.79 mmol, 120 equiv) and aq, 1N NaOH
(0.232 mL, 0.24 mmol). The resulting solution was stirred for 2 h
at 25.degree. C. The crude product was purified by Prep-HPLC with
the following conditions: Column: XBridge Prep C18 OBD,
19.times.150 mm, 5 .mu.m; Mobile Phase A: Water/0.1% Formic acid,
Mobile Phase B: CH.sub.3CN; Gradient: 5% B up to 20% B in 7 min;
Detector: UV 254 nm, 220 nm. The collected fractions were
lyophilized to afford 11.6 mg (39%, yield) of the title compound as
a light pink solid. .sup.1H NMR (300 MHz, DMSO-d6) .delta. (ppm):
11.13 (s, 1H), 9.04 (s, 1H), 7.58-7.53 (t, J=7.4 Hz, 2H), 7.27-7.24
(d, J=7.8 Hz, 1H), 3.35-3.31 (t, J=6.6 Hz, 2H), 3.17-3.11 (d,
J=16.2 Hz, 2H), 2.88-2.83 (d, J=16.2 Hz, 2H), 2.79 (s, 3H),
1.98-1.94 (t, J=6.6 Hz, 2H). MS: (ES, m/z): 261 [M+H]*.
Step-10: Methyl
(S)-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxyl-
ate
[0393] The procedure from Step 8 was followed using the second
eluted isomer from Step 7, which was assigned as methyl
(S)-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
as described above, (50 mg, 0.20 mmol, 1 equiv) to afford 53 mg
(94% yield) of the title compound as a light yellow oil. MS: (ES,
m/z): 260 [M+H].sup.+.
Step-11:
(S)--N-Hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide
[0394] The procedure from Step 9 was followed using methyl
(S)-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxyl-
ate (53 mg, 0.20 mmol, 1 equiv) to afford 20.9 mg (39% yield) of
the title compound as a white solid. .sup.1H NMR (300 MHz, DMSO-d6)
.delta. (ppm): 11.11 (m, 1H), 8.98 (s, 1H), 7.59-7.54 (m, 2H),
7.28-7.25 (m, 1H), 3.36-3.32 (m, 2H), 3.18-3.16 (d, J=3.3 Hz, 1H),
3.12-3.11 (d, J=3.0 Hz, 1H), 2.89 (s, 1H), 2.84 (s, 1H), 2.80-2.75
(m, 3H), 1.99-1.95 (m, 2H). MS: (ES, m/z): 261 [M+H].sup.+.
TABLE-US-00002 TABLE 1 The following compounds were prepared
according to the method of Example 1, with stereochemistry assigned
as described, with the following modifications: (1) In Steps 8 and
10, the halide can be an iodide, a chloride, or a bromide; (2) In
Steps 9 and 11, the Prep-HPLC column can be XBridge Prep C18 OBD,
19 .times. 150 mm, 5 .mu.m using formic acid or NH.sub.4HCO.sub.3
as the additive to the water Mobile Phase A; or the column XBridge
Shield RP18 OBD, 19 .times. 150 mm, 5 .mu.m using formic acid as
the additive to the water Mobile Phase A. Found (ES, m/z) Ex.
Structure .sup.1H-NMR .delta. (ppm) [M + H].sup.+ I-3 ##STR00011##
(400 MHz, DMSO-d6): 10.97 (s, 1H), 8.96 (s, 1H), 7.57 (s, 1H), 7.54
(d, J = 8.0 Hz, 1H), 7.23 (d, J = 16.8 Hz, 1H), 4.18-4.11 (m, 1H),
3.33-3.26 (m, 2H), 3.14-3.10 (d, J = 16.8 Hz, 2H), 2.87- 2.83 (d, J
= 16.0 Hz, 2H), 1.94-19.1 (m, 2 H), 1.11-1.09 (m, 6H) 289 I-4
##STR00012## (400 MHz, DMSO-d6): 11.09 (br, 1H), 8.96 (br, 1H),
7.58 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H),
4.19-4.11 (m, 1H), 3.30-3.26 (m, 2H), 3.13 (d, J = 16.0 Hz, 2H),
2.86 (d, J = 16.4 Hz, 2H), 1.95-1.92 (m, 2H), 1.15- 1.09 (m, 6H)
289 I-5 ##STR00013## (300 MHz, DMSO-d6): 8.55-8.41 (s, 2H),
7.58-7.53 (m, 2H), 7.26-7.24 (d, J = 8.0 Hz, 1H), 3.41-3.23 (m,
4H), 3.15- 3.10 (m 2H), 2.88-2.84 (d, J = 16.0 Hz, 2H), 1.96-1.93
(m, 2H), 1.07-1.03 (m, 3H) 275 I-6 ##STR00014## (400 MHz, DMSO-d6):
8.96 (br, 1H), 7.58 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.25 (d, J =
8.0 Hz, 1H), 3.35-3.30 (m, 2H), 3.28-3.16 (m, 2H), 3.15-3.11 (m,
2H), 2.88-2.84 (m, 2H), 2.08-1.94 (m, 2H), 1.15-1.02 (m, 3H) 275
I-7 ##STR00015## (400 MHz, DMSO-d6): 11.06 (s, 1H), 8.98 (s, 1H),
7.58 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H),
3.34-3.31 (m, 2H), 3.16-3.12 (m, 2H), 3.05-3.04 (m, 2H), 2.90-2.86
(m, 2H), 1.91-1.87 (m, 3H), 0.85-0.83 (m, 6H) 303 I-8 ##STR00016##
(400 MHz, DMSO-d6): 11.10 (br s, 1H), 8.98 (br s, 1H), 7.58 (s,
1H), 7.55 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 3.35 (s,
1H), 3.32 (s, 1H), 3.15 (d, J = 16.0 Hz, 2H), 3.06-3.04 (m, 2H),
2.89 (d, J = 12.0 Hz, 2H), 1.98-1.88 (m, 3H), 0.85-0.81 (m, 6H) 303
I-9 ##STR00017## (400 MHz, DMSO-d6): 11.02 (s, 1H), 9.02 (s, 1H),
7.59 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H),
7.21-7.12 (m, 4H), 4.44 (s, 2H), 3.22- 3.16 (m, 4H), 2.93-2.89 (m,
2H), 2.25 (s, 3H), 1.97-1.95 (m, 2H) 351 I-10 ##STR00018## (400
MHz, DMSO-d6): 11.12 (br, 1H), 8.97 (br, 1H) 7.60 (s, 1H), 7.55 (d,
J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.21-7.15 (m, 3H), 7.13
(d, J = 3.6 Hz, 1H), 4.44 (s, 2H), 3.22-3.16 (m, 4H), 2.92 (d, J =
16.0 Hz, 1H), 2.32 (s, 3H), 1.99-1.96 (m, 2H) 351 I-12 ##STR00019##
(300 MHz, DMSO-d6): 11.12 (s, 1H), 8.98 (s, 1H), 7.61-7.58 (m, 1H),
7.57- 7.55 (m, 1H), 7.41-7.37 (m, 2H), 7.57 7.31 (m, 1H), 7.30-7.23
(m, 3H), 4.45 (s, 2H), 3.27-3.23 (m, 2H), 3.19 (s, 1H), 2.95 (s,
1H), 2.90 (s, 1H), 2.08- 1.97 (m, 2H) 337
Example 2--Preparation of
(R)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]--
5-carboxamide (I-11)
##STR00020##
[0395] Step-1:
(R)-1'-Benzyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxyl-
ic acid
[0396] Into an 8-mL vial was placed a solution of the first eluted
isomer from Example 1, Step 7, which was assigned as methyl
(R)-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
as described above, (50 mg, 0.20 mmol, 1 equiv) in DMF (3 mL). The
reaction was cooled to 0.degree. C. and NaH (60% in mineral oil,
16.3 mg, 0.41 mmol) was added portionwise at 0.degree. C. The
resulting solution was stirred for 30 min at 0.degree. C.
(Bromomethyl)benzene (69.7 mg, 0.41 mmol) was added at 0.degree. C.
The reaction was stirred for 2 h at 25.degree. C. The reaction was
then poured into 10 mL water. The solution was adjusted to pH 2
with 2N HCl and extracted with EtOAc (2.times.10 mL). The organic
layers were combined, dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum to afford 40 mg (49% yield) of the title
compound as a yellow oil. MS: (ES, m/z): 322 [M+H].sup.+.
Step-2:
(R)-1'-Benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrol-
idine]-5-carboxamide
[0397] Into an 8-mL vial was placed
(R)-1'-benzyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxyl-
ic acid (40 mg, 0.12 mmol, 1 equiv) in DMA (3 mL). This was
followed by the addition of isopropyl chloroformate (78.7 mg, 0.64
mmol, 5 equiv) and NMM (63.1 mg, 0.62 mmol, 5 equiv) dropwise with
stirring at 0.degree. C. The resulting solution was stirred for 30
min at 0.degree. C. To the mixture was added a solution of
NH.sub.2OH.HCl (43.7 mg, 0.62 mmol, 5 equiv) in DMA (0.5 mL). The
reaction was stirred for 16 h at 25.degree. C. The solids were
filtered out and the crude product was purified by Prep-HPLC with
the following conditions: Column: XBridge Prep C18 OBD,
19.times.150 mm, 5 .mu.m; Mobile Phase A: Water/0.1% Formic acid.
Mobile Phase B: CH.sub.3CN; Gradient; 25% B up to 55% B in 7 min;
Detector: UV 254 nm, 220 nm. The collected fractions were
lyophilized to afford 16.9 mg (40% yield) of the title compound as
an off-white solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. (ppm):
11.10 (s, 1H), 8.98 (s, 1H), 7.60-7.54 (m, 2H), 7.40-7.23 (m, 6H),
4.44 (s, 2H), 3.25-3.18 (m, 4H), 2.93-2.89 (d, J=12 Hz, 2H),
1.99-1.92 (m, 2H). MS: (ES, m/z): 337 [M+H].sup.+.
Example 3--Preparation of
(R)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-13)
##STR00021##
[0398] Step-1: Methyl
(R)-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxyl-
ate
[0399] Into a 100-mL round-bottom flask was placed a solution of
the first eluted isomer from Example 1, Step 7, which was assigned
as methyl
(R)-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
as described above, (50 mg, 0.20 mmol, 1 equiv) in CH.sub.2Cl.sub.2
(10 mL). Cu(OAc).sub.2 (69.8 mg, 0.380 mmol, 2 equiv), Et.sub.3N
(58.2 mg, 0.58 mmol, 3 equiv), phenylboronic acid (117 mg, 0.96
mmol, 5 equiv) and 4 .ANG. molecular sieves (100 mg) were added.
O.sub.2 (g) was introduced to the reaction mixture. The resulting
solution was stirred for 60 h at 25.degree. C. The solids were
filtered out and the filtrate was diluted with 10 mL of water and
extracted with CH.sub.2Cl.sub.2 (3.times.10 mL). The combined
organic layers were dried over Na.sub.2SO.sub.4 and concentrated
under vacuum to afford 20 mg (29% yield) of the title compound as
an orange oil. MS: (ES, m/z): 322 [M+H].sup.+.
Step-2:
(R)--N-Hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrro-
lidine]-5-carboxamide
[0400] Into an 8-mL vial was placed a solution of methyl
(R)-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxyl-
ate (20 mg, 0.06 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL). Then
NH.sub.2OH (50% in water, 492 mg, 7.45 mmol, 120 equiv) was added
followed by aq. 1N NaOH (0.124 mL, 2 equiv). The resulting solution
was stirred for 2 h at 25.degree. C. The crude product was purified
by Prep-HPLC with the following conditions: Column: XBridge Prep
C18 OBD, 19.times.150 mm, 5 .mu.m; Mobile Phase A: Water/0.1%
Formic acid, Mobile Phase B: CH.sub.3CN; Gradient: 5% B up to 57% B
in 7 min; Detector: UV 254 nm, 220 nm. The collected fractions were
lyophilized to afford 6.7 mg (33% yield) of the title compound as a
white solid. .sup.1H NMR (300 MHz, DMSO-d6) .delta. (ppm): 10.88
(s, 1H), 9.00 (s, 1H), 7.73-7.71 (d, J=7.8 Hz, 2H), 7.61-7.56 (t,
J=8.4 Hz, 6H), 7.42-7.37 (t, J=8.0 Hz, 2H), 7.30-7.27 (d, J=7.8 Hz,
1H), 7.18-7.13 (t, 0.1=7.4 Hz, 1H), 3.89-3.84 (t, J=6.8 Hz, 2H),
3.24 (s, 2H), 3.05-2.99 (d, 0.1=16.2 Hz, 2H), 2.15-2.07 (m, 2H).
MS: (ES, m/z): 323 [M+H].sup.+.
Example 4--Preparation of
(S)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide (I-14)
##STR00022##
[0401] Step-1: Methyl
(S)-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxyl-
ate
[0402] Into a 25-mL round-bottom flask was placed a solution of the
second eluted isomer from Example 1, Step 7, which was assigned as
methyl
(S)-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
as described above, (50 mg, 0.20 mmol, 1 equiv) in THF (8.0 mL).
Cu(OAc).sub.2 (37 mg, 0.20 mmol, 1 equiv), Et.sub.3N (62 mg, 0.61
mmol, 3 equiv), pyridine (24 mg, 0.31 mmol, 1.5 equiv),
phenylboronic acid (49.7 mg, 0.41 mmol, 2 equiv) and 4 .ANG.
molecular sieves were added. O.sub.2 (g) was introduced in. The
resulting solution was stirred for 18 h at 60.degree. C. in an oil
bath. The solids were filtered out and the filtrate was
concentrated under vacuum. The residue was dissolved in 60 mL of
EtOAc and was washed with 3.times.20 mL of H.sub.2O. The organic
layer was separated and concentrated under vacuum. The residue
purified by normal phase chromatography on silica gel using
EtOAc/petroleum ether (1:2). The collected fractions were
concentrated under vacuum to afford 60 mg (92%) of the title
compound as a light yellow oil. MS: (ES, m/z): 322 [M+H].sup.+.
Step-2:
(S)--N-Hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrro-
lidine]-5-carboxamide
[0403] Into an 8-mL vial was placed a solution of methyl
(S)-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxyl-
ate (60 mg, 0.19 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL). Then
NH.sub.2OH (50% in water, 274 mg, 5.37 mmol, 30 equiv) was added
followed by aq 1N NaOH (0.37 mL, 2 equiv). The resulting solution
was stirred for 1 h at 25.degree. C. The crude product was purified
by Prep-HPLC with the following conditions: Column: XBridge Prep
C18 OBD, 19.times.150 mm, 5 .mu.m; Mobile Phase A: Water/0.1%
Formic acid, Mobile Phase B: CH.sub.3CN; Gradient: 5% B up to 57% B
in 7 min; Detector: UV 254 nm, 220 nm. The collected fractions were
lyophilized to afford 24.3 mg (40% yield) of the title compound as
an off-white solid. .sup.1H NMR (300 MHz, DMSO-d6) .delta. (ppm):
11.14 (s, 1H), 9.00 (s, 1H), 7.75-7.72 (m, 2H), 7.63-7.57 (m, 2H),
7.44-7.38 (m, 2H), 7.32-7.29 (m, 1H), 7.19-7.14 (m, 1H), 3.90-3.86
(m, 2H), 3.34-3.25 (m, 2H), 3.06-3.01 (d, 0.1=16.2 Hz, 2H),
2.16-2.08 (m, 2H). MS: (ES, m/z): 323 [M+H].sup.+.
TABLE-US-00003 TABLE 2 The following compounds were prepared
according to the method of Example 4, with stereochemistry assigned
as described, with the following modifications: In Prep-HPLC
purification of Step 2, formic acid or NH.sub.4HCO.sub.3 can be
used as the additive to the water Mobile Phase A. Found (ES, m/z)
Ex. Structure .sup.1H-NMR .delta. (ppm) [M + H].sup.+ I-15
##STR00023## (400 MHz, DMSO-d6): 10.71 (s, 1H), 8.95 (s, 1H),
7.74-7.71 (m, 2H), 7.60- 7.54 (m, 2H), 7.28-7.20 (m, 3H), 3.85-
3.82 (m, 2H), 3.30-63.22 (m, 2H), 3.02- 2.98 (m, 2H), 2.12-2.09 (m,
2H) 341 I-16 ##STR00024## (400 MHz, DMSO-d6): 11.10 (br s, 1H),
8.98 (br s, 1H), 7.77-7.73 (m, 2H), 7.62 (s, 1H), 7.57 (d, J = 7.6
Hz 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.27-7.22 (m, 2H), 3.88-3.84 (m,
2H), 3.29-3.23 (m, 2H), 3.04-3.00 (m, 2H), 2.14-2.11 (m, 2H) 341
I-18 ##STR00025## (400 MHz, DMSO-d6): 8.95-8.94 (m, 2H), 8.37-8.36
(m, 1H), 8.17-8.15 (m, 1H), 7.62 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H),
7.46-7.42 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 3.93-3.90 (m, 2H),
3.32-3.29 (m, 1H), 3.26-3.25 (m, 1H), 3.07-3.02 (m, 2H), 2.19-2.07
(m, 2H) 324
Example 5--Preparation of
(R)--N-hydroxy-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3'-pyrr-
olidine]-5-carboxamide (I-17)
##STR00026##
[0404] Step-1: Methyl
(R)-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5--
carboxylate
[0405] Into a 10-mL sealed tube was placed a solution of the first
eluted isomer from Example 1, Step 7, which was assigned as methyl
(R)-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
as described above, (60 mg, 0.24 mmol, 1 equiv) in toluene (5 mL),
3-bromopyridine (77 mg, 0.49 mmol, 2 equiv), RuPhos (23 mg, 0.05
mmol), Cs.sub.2CO.sub.3 (240 mg, 0.74 mmol, 3 equiv) and RuPhos Pd
G2 (19 mg, 0.02 mmol, 0.1 equiv). The reaction was stirred for 16 h
at 110.degree. C. The reaction mixture was then cooled to room
temperature and poured into 15 mL of water. The resulting solution
was extracted with 3.times.30 mL of EtOAc. The combined organic
layers were washed with 100 mL of brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The
residue was purified by normal phase chromatography on silica gel
using EtOAc/petroleum ether (1:1). The collected fractions were
concentrated under vacuum to afford 51 mg (60% yield) of the title
compound as a yellow oil. MS: (ES, m/z): 323 [M+H].sup.+.
Step-2:
(R)--N-Hydroxy-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,-
3'-pyrrolidine]-5-carboxamide
[0406] Into a 25-mL round-bottom flask was placed methyl
(R)-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5--
carboxylate (51 mg, 0.16 mmol, 1 equiv), THF/MeOH (4:1, 4 mL),
NH.sub.2OH (50% in water, 1426 mg, 43.17 mmol, 120 equiv) and aq.
1N NaOH (0.32 mL, 0.32 mmol, 2 equiv). The resulting solution was
stirred for 2 h at room temperature. The solids were filtered out
and the crude product was purified by Prep-HPLC with the following
conditions: Column: XBridge Prep C18 OBD, 19.times.150 mm, 5 .mu.m;
Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B: CH.sub.3CN,
Gradient: 5% B up to 14% B in 8 min, Detector: UV 254 nm, 220 nm.
The collected fractions were lyophilized to afford 20.1 mg (39%
yield) of the title compound as an off-white solid. .sup.1H NMR
(300 MHz, DMSO-d6) .delta. (ppm): 8.94 (s, 1H), 8.37 (d, J=3.9 Hz,
1H), 8.17 (d, J=20.4 Hz, 1H), 7.61-7.56 (m, 2H), 7.50-7.46 (m, 1H),
7.34 (d, J=7.8 Hz, 1H), 3.93 (d, J=6.6 Hz, 2H), 3.29 (d, J=16.5 Hz,
2H), 3.07 (d, J=16.2 Hz, 2H), 2.20-2.16 (m, 2H). MS: (ES, m/z): 324
[M+H].sup.+.
TABLE-US-00004 TABLE 3 The following compounds were prepared
according to the method of Example 5, with stereochemistry assigned
as described, with the following modifications: In Prep-HPLC
purification of Step 2, formic acid or NH.sub.4HCO.sub.3 can be
used as the additive to the water Mobile Phase A. Found (ES, m/z)
Ex. Structure .sup.1H-NMR .delta. (ppm) [M + H].sup.+ I-19
##STR00027## (300 MHz, DMSO-d6): 11.11 (s, 1H), 8.98 (s, 1H),
8.43-8.41 (m, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.86-7.81 (m, 1H),
7.62-7.57 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.19-7.15 (m, 1H),
4.05-4.00 (m, 2H), 3.30 (d, J = 17.7 Hz, 2H), 3.08 (d, J = 16.5 Hz,
2H), 2.14-2.08 (m, 2H) 324 I-20 ##STR00028## (400 MHz, DMSO-d6):
8.43-8.41 (m, 1H), 8.34-8.32 (m, 1H), 7.86-7.81 (m, 1H), 7.62 (s,
1H), 7.58 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.19- 7.15
(m, 1H), 4.04-4.01 (m, 2H), 3.32-3.27 (m, 2H), 3.07-3.03 (m, 2H),
2.14-2.07 (m, 2H) 324 I-21 ##STR00029## (300 MHz, DMSO-d6): 11.11
(s, 1H), 9.00 (d, J = 11.4 Hz, 1H), 8.52 (d, J = 6.3 Hz, 2H),
7.75-7.73 (m, 2H), 7.62- 7.57 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H),
3.91-3.86 (m, 2H), 3.32-3.30 (m, 1H), 3.25 (s, 1H), 3.08 (s, 1H),
3.02 (s, 1H), 2.18-2.07 (m, 2H) 324 I-22 ##STR00030## (400 MHz,
DMSO-d6): 11.12 (br s, 1H), 8.96 (br s, 1H), 8.53-8.51 (m, 2H),
7.75-7.73 (m, 2H), 7.62 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H),7.29 (d,
J = 8.0 Hz, 1H), 3.90-3.87 (m, 2H), 3.29-3.25 (m, 2H), 3.07-3.03
(m, 2H), 2.18-2.07 (m, 2H) 324
Example 6--Preparation of
(R)--N-hydroxy-2'-oxo-1'-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3-
'-pyrrolidine]-5-carboxamide (I-23)
##STR00031##
[0407] Step-1: Methyl
(R)-2'-oxo-1'-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3'-pyrrolidi-
ne]-5-carboxylate
[0408] Into a 25-mL round-bottom flask was placed a solution of the
first eluted isomer from Example 1, Step 7, which was assigned as
methyl
(R)-2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
as described above, (50 mg, 0.20 mmol, 1 equiv) in DMF (3 mL). NaH
(60% in mineral oil, 16 mg, 0.40 mmol, 2 equiv) was then added at
0.degree. C. The resulting solution was stirred for 30 min at
0.degree. C. A solution of 3-(bromomethyl) pyridine hydrobromide
(77 mg, 0.30 mmol, 1.5 equiv) and Et.sub.3N (61 mg, 0.60 mmol, 3
equiv) in DMF (1 mL) were added dropwise with stirring at 0.degree.
C. The resulting solution was allowed to stir for 1 h at room
temperature. The reaction mixture was then poured into 15 mL of ice
water and extracted with 3.times.15 mL of EtOAc. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum to afford 55 mg of the title compound as
a yellow oil. MS: (ES, m/z): 337 [M+H].sup.+.
Step-2:
(R)--N-Hydroxy-2'-oxo-1'-(pyridin-3-ylmethyl)-1,3-dihydrospiro[ind-
ene-2,3'-pyrrolidine]-5-carboxamide
[0409] Into a 25-mL round-bottom flask was placed methyl
(R)-2'-oxo-1'-(pyridin-3-ylmethyl)-1,3-dihydrospiro[indene-2,3'-pyrrolidi-
ne]-5-carboxylate (55 mg, 0.16 mmol, 1 equiv), THF/MeOH (4:1, 3.0
mL), NH.sub.2OH (50% in water, 648 mg, 9.81 mmol, 60 equiv) and aq.
1N NaOH (0.32 mL, 0.32 mmol, 2 equiv). The resulting solution was
stirred for 2 h at 25.degree. C. The solids were filtered and the
crude product was purified by Prep-HPLC with the following
conditions: Column: XBridge Prep C18 OBD, 19.times.150 mm, 5 .mu.m;
Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B: CH.sub.3CN;
Gradient: 3% B up to 23% B in 7 min; Detector: UV 254 nm, 220 nm.
The collected fractions were lyophilized to afford 19.6 mg (36%
yield) of the title compound as a light pink solid. .sup.1H NMR
(400 MHz, DMSO-d6) .delta. (ppm): 11.05 (s, 1H), 8.95 (s, 1H),
8.51-8.47 (m, 2H), 7.64-7.52 (m, 3H), 7.40-7.39 (m, 1H), 7.37-7.24
(m, 1H), 4.46 (s, 2H), 3.27-3.24 (m, 2H), 3.19-3.15 (d, 0.1=16.4
Hz, 2H), 2.92-2.88 (d, J=16.4 Hz, 2H), 1.99-1.95 (m, 2H) MS: (ES,
m/z); 338 [M+H].sup.+.
Example 7--Preparation of
(R)--N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carb-
oxamide and
(S)--N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carb-
oxamide (I-24 and I-25)
##STR00032##
[0410] Step-1: Methyl
2'-thioxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0411] Into a 100-mL round-bottom flask was placed methyl
2'-oxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate (2.4
g, 9.78 mmol, 1 equiv), CH.sub.2Cl.sub.2 (30 mL) and
2,4-bis(4-methoxyphenyl)-2,4-dithioxo-, 3,2,4-dithiadiphosphetane
(Lawesson reagent) (5.9 g, 14.59 mmol, 1.5 equiv). The resulting
solution was stirred for 16 h at room temperature. The reaction was
then quenched by the addition of aq NaHCO.sub.3 (30 mL). The
resulting solution was extracted with 3.times.30 mL of
CH.sub.2Cl.sub.2. The organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The
residue was purified by normal phase column chromatography on
silica gel using EtOAc/petroleum ether (1:1). The collected
fractions were concentrated under vacuum to afford 2 g (78% yield)
of the title compound as a yellow solid. MS: (ES, m/z): 262
[M+H].sup.+.
Step-2: Methyl
1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0412] Into a 100-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed methyl
2'-thioxo-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
(2 g, 7.65 mmol, 1 equiv), THF (40 mL), MeOH (10 mL) and
NiCl.sub.2.6H.sub.2O (10.9 g, 45.86 mmol, 6 equiv). This was
followed by the addition of NaBH.sub.4 (1.74 g, 45.99 mmol, 6
equiv) in several batches at 0.degree. C. The resulting solution
was stirred for 18 h at room temperature. The reaction was
concentrated under vacuum. The residue was dissolved in 10 mL of
THF and filtered through a Celite pad. The filtrate was
concentrated under reduced pressure and the residue was purified by
normal phase column chromatography on silica gel using
CH.sub.2Cl.sub.2/MeOH (10:1). The collected fractions were
concentrated under vacuum to afford 1.4 g (79% yield) of the title
compound as a green solid. MS: (ES, m/z): 232 [M+H].sup.+.
Step-3: 1'-(tert-Butyl) 5-methyl
(R)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-1',5-dicarboxylate
and 1'-(tert-Butyl) 5-methyl
(S)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-1',5-dicarboxylate
[0413] Into a 50-mL round-bottom flask was placed methyl
1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate (1.4 g,
6.05 mmol, 1 equiv), CH.sub.2Cl.sub.2 (15 mL), Et.sub.3N (2.4 g,
23.72 mmol, 4 equiv) and di-tert-butyl dicarbonate (3.3 g, 15.12
mmol, 2.5 equiv). The resulting solution was stirred for 18 h at
room temperature. The reaction was then quenched by the addition of
20 mL of water. The resulting solution was extracted with
3.times.20 mL of CH.sub.2C.sub.12. The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered, concentrated under vacuum,
and the residue was purified by normal phase column chromatography
on silica gel using EtOAc/petroleum ether (1:10) to afford the
racemic mixture of the title compounds. The racemate was further
separated by Prep-SFC with the following conditions: Column:
EnantioCel-C1, 21.2.times.250 mm; Mobile Phase A: CO.sub.2, Mobile
Phase B: EtOH; Gradient 20% B; Flow rate: 40 mL/min; Detector: UV
220 nm. The first eluting isomer (Rt 4.91 min) was collected and
concentrated under vacuum to give 400 mg (20% yield) of a white
solid which was assigned as the R isomer of 1'-(tert-butyl)
5-methyl
1,3-dihydrospiro[indene-2,3'-pyrrolidine]-1',5-dicarboxylate. MS:
(ES, m/z): 332 [M+H].sup.+. The second eluting isomer (Rt 5.76 min)
was collected and concentrated under vacuum to give 400 mg (20%
yield) of a white solid which was assigned as the S isomer of
1'-(tert-butyl) 5-methyl
1,3-dihydrospiro[indene-2,3'-pyrrolidine]-1',5-dicarboxylate. MS:
(ES, m/z): 332 [M+H].sup.+.
Step-4: Methyl
(R)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0414] Into a 25-mL round-bottom flask was placed the first eluted
isomer from Step 3, which was assigned as 1'-(tert-butyl) 5-methyl
(R)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-1',5-dicarboxylate as
described above, (400 mg, 1.21 mmol, 1 equiv), CH.sub.2Cl.sub.2 (8
mL) and TFA (2 mL). The reaction was stirred for 2 h at room
temperature. The reaction was concentrated under vacuum. The
residue was dissolved in water (10 mL) and the pH was adjusted to 8
with aq. NaHCO.sub.3. The resulting solution was extracted with
3.times.15 mL of CH.sub.2Cl.sub.2. The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum
to afford 270 mg (97% yield) of the title compound as a yellow oil.
MS: (ES, m/z): 232 [M+H].
Step-5: Methyl
(R)-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0415] Into a 10-mL round-bottom flask was placed methyl
(R)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate (50 mg,
0.22 mmol, 1 equiv), MeOH (3 mL) and paraformaldehyde (7.8 mg, 0.26
mmol, 1.2 equiv). The resulting solution was stirred for 1 h at
room temperature. This was followed by the addition of NaBH.sub.3CN
(42 mg, 0.67 mmol, 3 equiv) in several batches at 0.degree. C. The
reaction was allowed to stir for 18 h at room temperature. The
reaction was poured into 15 mL of water. The resulting solution was
extracted with 3.times.15 mL of EtOAc. The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, and concentrated under
vacuum. The residue was purified by normal phase column
chromatography on silica gel using EtOAc/petroleum ether (1:2). The
collected fractions were concentrated under vacuum to afford 50 mg
(94% yield) of the title compound as a yellow oil. MS: (ES, m/z):
246 [M+H].sup.+.
Step-6:
(R)--N-Hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide
[0416] Into a 10-mL round-bottom flask was placed methyl
(R)-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
(50 mg, 0.20 mmol, 1 equiv), THF/MeOH (4:1, 5.0 mL), NH.sub.2OH
(50% in water, 1.58 g, 24 mmol, 120 equiv) and aq. 1N NaOH (16.3
mg, 0.41 mmol, 2 equiv). The resulting solution was stirred for 2 h
at room temperature. The solids were filtered and the crude product
was purified by Prep-HPLC with the following conditions: Column:
XBridge Shield RP18 OBD, 19.times.150 mm, 5 .mu.m, Mobile Phase A:
Water/NH.sub.4HCO.sub.3, Mobile Phase B: CH.sub.3CN; Gradient: 0% B
up to 18% B in 7 min; Detector: UV 220 nm, 254 nm. The collected
fractions were lyophilized to afford 7.9 mg (16% yield) of the
title compound as a white solid. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. (ppm): 7.55 (s, 1H), 7.50 (d, J=8 Hz, 1H), 7.21 (d, J=7.6
Hz, 1H), 2.97-2.84 (m, 2H), 2.55-2.51 (m, 2H), 2.40 (s, 2H), 2.23
(s, 3H), 1.81-1.77 (m, 2H). MS: (ES, m/z): 247 [M+H].sup.+.
Step-7: Methyl
(S)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0417] The procedure from Step 4 was followed using the second
eluted isomer from Step 3, which was assigned as 1'-(tert-butyl)
5-methyl
(S)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-1',5-dicarboxylate as
described above, (470 mg, 1.42 mmol, 1 equiv) to afford 230 mg (70%
yield) of the title compound as a yellow oil. MS: (ES, m/z): 232
[M+H].sup.+.
Step-8: Methyl
(S)-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0418] The procedure from Step 5 was followed using methyl
(S)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate (50 mg,
0.22 mmol, 1 equiv) to afford 27 mg (51% yield) of the title
compound as a yellow oil. MS: (ES, m/z): 246 [M+H].sup.+.
Step-9:
(S)--N-Hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
-5-carboxamide
[0419] The procedure from Step 6 was followed using methyl
(S)-1'-methyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
(27 mg, 0.11 mmol, 1 equiv) to afford 9.2 mg (34% yield) of the
title compound as a white solid. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. (ppm); 7.55 (s, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.6
Hz, 1H), 2.95 (d, J=16.0 Hz, 2H), 2.86 (d, J=16.0 Hz, 2H),
2.56-2.51 (m, 2H), 2.42-2.39 (m, 2H), 2.23-2.21 (m, 3H), 1.80-1.77
(m, 2H). MS: (ES, m/z): 247 [M+H].sup.+.
TABLE-US-00005 TABLE 4 The following compounds were prepared
according to the method of Example 7, with stereochemistry assigned
as described, with the following modifications: In Prep-HPLC
purification of Steps 6 and 9, formic acid or NH.sub.4HCO.sub.3 can
be used as the additive to the water Mobile Phase A. Found (ES,
m/z) Ex. Structure .sup.1H-NMR .delta. (ppm) [M + H].sup.+ I-26
##STR00033## (400 MHz, DMSO-d6): 11.08 (s, 1H), 8.19 (s, 1H),
7.55-7.49 (m, 2H), 7.32 (d, J = 4.2 Hz, 4H), 7.29-7.22 (m, 2H),
3.63 (s, 2H), 2.99-2.86 (m, 4H), 2.69- 2.65 (m, 2H), 2.51 (s, 2H),
1.86-1.81 (m, 2H) 323 I-27 ##STR00034## (400 MHz, DMSO-d6): 11.07
(s, 1H), 8.18 (s, 1H), 7.54-7.48 (m, 2H), 7.32- 7.28 (m, 4H),
7.25-7.15 (m, 2H), 3.64 3.60 (m, 2H), 2.95 (d, J = 16.0 Hz, 2H),
2.88 (d, J = 16.0 Hz, 2H), 2.69-2.63 (m, 2H), 2.49-2.46 (m, 2H),
1.84-1.80 (m, 2H) 323
Example 8--Preparation of
(S)-1'-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carbo-
xamide (I-29)
##STR00035##
[0420] Step-1: Methyl
(S)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0421] Into a 50-mL round-bottom flask was placed the second eluted
isomer from Example 7 Step 3, which was assigned as 1'-(tert-butyl)
5-methyl
(S)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-1',5-dicarboxylate as
described above, (470 mg, 1.42 mmol, 1 equiv), TFA (5 mL) and
CH.sub.2Cl.sub.2 (15 mL). The resulting solution was stirred for 2
h at room temperature. The resulting mixture was washed with
3.times.30 mL of aq NaHCO.sub.3, dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum to afford 230 mg (70% yield)
of the title compound as a yellow oil. MS: (ES, m/z): 232
[M+H].sup.+.
Step-2: Methyl
(S)-1'-acetyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
[0422] Into a 10-mL vial was placed methyl
(S)-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate (50 mg,
0.22 mmol, 1 equiv) and CH.sub.2C.sub.2 (5 mL). This was followed
by the addition of Et.sub.3N (109 mg, 1.08 mmol, 5 equiv) dropwise
at 0.degree. C. Acetyl chloride (51 mg, 0.65 mmol, 3 equiv) was
added dropwise at 0.degree. C. The resulting solution was stirred
for 2 h at room temperature. The reaction mixture was poured into
20 mL of ice water and extracted with 3.times.30 mL of EtOAc. The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated under vacuum to afford 52 mg of the title compound
as a yellow oil. MS: (ES, m/z): 274 [M+H].sup.+.
Step-3:
(S)-1'-Acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]--
5-carboxamide
[0423] Into a 25-mL round-bottom flask was placed methyl
(S)-1'-acetyl-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxylate
(62 mg, 0.23 mmol, 1 equiv), THF/MeOH (4:1, 2.0 mL), NH.sub.2OH
(50.degree. % in water, 896 mg, 13.56 mmol, 60 equiv) and aq. 1N
NaOH (0.45 mL, 0.45 mmol, 2 equiv). The resulting solution was
stirred for 2 h at room temperature. The solids were filtered and
the crude product was purified by Prep-HPLC with the following
conditions; Column: XBridge Prep C18 OBD, 19.times.150 mm, 5 .mu.m;
Mobile Phase A: Water/0.1% Formic acid, Mobile Phase B: CH.sub.3CN;
Gradient: 5% B up to 30% B in 7 min; Detector: UV 254 nm, 220 nm.
The collected fractions were lyophilized to afford 13.6 mg (22%
yield) of the title compound as a yellow solid. .sup.1H NMR (300
MHz, DMSO-d6) .delta. (ppm): 11.07 (s, 1H), 9.09 (s, 1H), 7.59-7.54
(m, 2H), 7.27-7.24 (m, 1H), 3.56-3.52 (m, 1H), 3.41-3.26 (m, 3H),
2.98-2.86 (m, 4H), 1.94-1.79 (m, 5H). MS: (ES, m/z): 275
[M+H].sup.+.
TABLE-US-00006 TABLE 5 The following compounds were prepared
according to the method of Example 8, with stereochemistry assigned
as described, with the following modifications: In Step 3 the
Prep-HPLC column can be XBridge Prep C18 OBD, 19 .times. 150 mm, 5
.mu.m using formic acid or NH.sub.4HCO.sub.3 as the additive to
OBD, the water Mobile Phase A; or the column XBridge Shield RP18 19
.times. 150 mm, 5 .mu.m using formic acid as the additive to the
water Mobile Phase A. Found (ES, m/z) Ex. Structure .sup.1H-NMR
.delta. (ppm) [M + H].sup.+ I-28 ##STR00036## (400 MHz, DMSO-d6):
11.11 (br s, 1H), 8.99) (s, 1H), 7.60-7.54 (m, 2H), 7.29-7.24 (m,
1H), 3.59-3.54 (m, 1H), 3.40 (d, J = 6.9 Hz, 2H), 3.28 (s, 1H),
2.92 (d, J = 7.5 Hz, 4H), 1.96-1.82 (m, 5H) 275 I-30 ##STR00037##
(400 MHz, DMSO-d6): 11.09 (br s, 1H), 8.97 (s, 1H), 7.56-7.40 (m,
7H), 7.30-7.20 (m, 1H), 3.62-3.49 (m, 3H), 3.36 (s, 1H), 3.01-2.91
(m, 2H), 2.87 (d, J = 7.6 Hz, 2H), 1.97-1.86 (m, 2H) 337 I-31
##STR00038## (300 MHz, DMSO-d6): 11.09 (s, 1H), 8.97 (s, 1H),
7.60-7.39 (m, 7H), 7.29- 7.19 (m, 1H), 3.74-3.71 (m, 1H), 3.63-3.59
(m, 2H), 3.48-3.32 (m, 1H), 3.15-2.80 (m, 4H), 1.97-1.84 (m, 2H)
337
Example 9--Preparation of
(R)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide and
(S)--N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide (I-32 and I-33)
##STR00039##
[0424] Step-1: Dimethyl
2-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate
[0425] Into a 250-mL round-bottom flask was placed dimethyl
1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate (4.4 g, 17.73 mmol, 1
equiv), DMF (50 mL), Et.sub.3N (5.3 g, 53.18 mmol, 3 equiv) and
prop-2-enenitrile (2.3 g, 44.31 mmol, 2.5 equiv). The resulting
solution was stirred for 16 h at 25.degree. C. The reaction was
diluted with 100 mL of water and extracted with 3.times.100 mL of
EtOAc. The organic layers were combined, washed with brine
(2.times.50 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum. The residue was purified by normal phase
chromatography on silica gel using EtOAc/petroleum ether (1:3). The
collected fractions were concentrated under vacuum to afford 2.0 g
(37% yield) of title compound as a yellow solid. MS: (ES, m/z): 302
[M+H].sup.+.
Step-2: Dimethyl
2-(3-aminopropyl)-1-hydroxy-2,3-dihydro-1H-indene-2,5-dicarboxylate
[0426] Into a 250-mL round-bottom flask was placed dimethyl
2-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-indene-2,5-dicarboxylate (1
g, 3.32 mmol, 1 equiv), MeOH (80 mL), PtO.sub.2 (1 g, 4.40 mmol,
1.33 equiv) and AcOH (20 mL). H.sub.2 was introduced to the flask
and the reaction was stirred for 1 h at 25.degree. C. The solids
were filtered out and the filtrate was concentrated under vacuum to
afford 900 mg of title compound as a brown oil. MS: (ES, m/z): 308
[M+H].sup.+.
Step-3: Methyl
1-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate
[0427] Into a 250-mL round-bottom flask was placed dimethyl
2-(3-aminopropyl)-1-hydroxy-2,3-dihydro-1H-indene-2,5-dicarboxylate
(1 g, 3.25 mmol, 1 equiv). A solution of 7M NH.sub.3 in MeOH (30
mL) was added dropwise with stirring at 0.degree. C. The resulting
solution was stirred for 1 h at 25.degree. C. The reaction was
concentrated under vacuum. The residue purified by normal phase
chromatography on silica gel using CH.sub.2Cl.sub.2/MeOH (20:1).
The collected fractions were concentrated under vacuum to afford 1
g of the title compound as a brown oil. MS: (ES, m/z): 276
[M+H].sup.+.
Step-4: Methyl
(R)-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate
and Methyl
(S)-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate
[0428] Into a 100-mL round-bottom flask was placed methyl
1-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate
(1 g, 3.63 mmol, 1 equiv), TFA (25 mL) and triethylsilane (25 mL).
The resulting solution was stirred overnight at 80.degree. C. in an
oil bath. After cooling to room temperature, the reaction was
concentrated under vacuum. The residue purified by normal phase
chromatography on silica gel using EtOAc/petroleum ether (99:1).
The product was purified by Chiral-Prep-HPLC with the following
conditions: Column: Phenomenex Lux.RTM. Cellulose-4 AXIA.TM.
Packed, 250.times.21.2 mm, 5 .mu.m; Mobile Phase A: hexanes, Mobile
Phase B: EtOH; Gradient: 30% B in 23 min; Detector: UV 254 nm, 220
nm. The first eluting isomer (Rt 2.8 min) was collected and
concentrated under vacuum to give 310 mg (33% yield) of an
off-white solid which was assigned as the R isomer of methyl
2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate. MS:
(ES, m/z): 260 [M+H].sup.+. The second eluting isomer (Rt 3.8 min)
was collected and concentrated under vacuum to give 280 mg (30%
yield) of an off-white solid which was assigned as the R isomer of
methyl
2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate. MS:
(ES, m/z): 260 [M+H].sup.+.
Step-5: Methyl
(R)-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxyla-
te
[0429] Into a 10-mL vial purged and maintained with an inert
atmosphere of nitrogen, was placed a solution of the first eluted
isomer from Step 4, which was assigned as methyl
(R)-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate
as described above, (50 mg, 0.19 mmol, 1 equiv) in DMF (2 mL). The
solution was cooled to 0.degree. C. and NaH (60%, in mineral oil,
31 mg, 0.78 mmol, 4 equiv) was added. The mixture was allowed warm
to room temperature and stirred for 30 min. CH.sub.3I (109 mg, 0.77
mmol, 4 equiv) was added and the reaction was stirred for 2 h at
25.degree. C. The reaction was then quenched by the addition of 20
mL of water and extracted with 3.times.20 mL of EtOAc. The organic
layers were combined, washed with 2.times.50 mL of brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated under vacuum to
afford 70 mg (crude) of title compound as a brown oil. MS: (ES,
m/z): 274 [M+H].sup.+.
Step-6:
(R)--N-Hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piper-
idine]-5-carboxamide
[0430] Into a 25-mL round-bottom flask was placed methyl
(R)-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxyla-
te (70 mg, 0.26 mmol, 1 equiv), THF/MeOH (4:1, 2.0 mL), NH.sub.2OH
(50% in water, 2023 mg, 120 equiv) and aq. 1N NaOH (0.51 mg, 2
equiv). The resulting solution was stirred for 2 h at 25.degree. C.
The solids were filtered out and the crude product was purified by
Prep-HPLC with the following conditions: Column: XBridge Prep C18
OBD, 19.times.150 mm 5 .mu.m; Mobile Phase A: Water/0.05% Formic
acid, Mobile Phase B: CH.sub.3CN; Gradient: 5% B up to 14% B in 7
min; Detector: UV 254 nm, 220 nm. The collected fractions were
lyophilized to afford 6.5 mg (9% yield) of the title compound as an
off-white solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. (ppm):
10.76 (s, 1H), 8.98 (s, 1H), 7.55-7.52 (t, J=6.2 Hz, 2H), 7.23-7.21
(d, J=8.0 Hz, 1H), 3.39-3.31 (m, 4H), 2.86-2.81 (m, 5H), 1.82-1.72
(m, 4H). MS: (ES, m/z): 275 [M+H].sup.+.
Step-7: Methyl
(S)-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxyla-
te
[0431] The procedure from Step 5 was followed using the second
eluted isomer from Step 4, which was assigned as methyl
(S)-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate
as described above, (50 mg, 0.19 mmol, 1 equiv) to afford 40 mg
(crude) of the title compound as a yellow solid. MS: (ES, m/z): 274
[M+H].sup.+.
Step-8:
(S)--N-Hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piper-
idine]-5-carboxamide
[0432] The procedure from Step 6 was followed using methyl
(S)-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxyla-
te (75 mg, 0.27 mmol, 1 equiv) to afford 13.4 mg (18% yield) of the
title compound as a pink solid. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. (ppm): 11.08 (s, 1H), 8.96 (s, 1H), 7.55 (s, 1H), 7.54-7.52
(d, J=7.6 Hz, 1H), 7.23-7.21 (d, J=7.6 Hz, 1H), 3.40 (s, 1H),
3.38-3.35 (d, J=9.2 Hz, 2H), 3.31 (s, 1H), 2.86-2.81 (m, 5H),
1.82-1.72 (m, 4H). MS: (ES, m/z): 275 [M+H].sup.+.
Example 10--Preparation of
(R)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-
-carboxamide (I-34)
##STR00040##
[0433] Step-1:
(R)-1'-Benzyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxyli-
c acid
[0434] Into a 10-mL 4-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of the first eluted isomer from Example 9 Step 4, which
was assigned as methyl
(R)-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate
as described above, (50 mg, 0.19 mmol, 1 equiv) in DMF (2 mL). This
was followed by the portionwise addition of NaH (60% in mineral
oil, 31 mg, 0.78 mmol, 4 equiv) at 0.degree. C. The mixture was
stirred for 30 min at 25.degree. C. (Bromomethyl)benzene (36 mg,
0.21 mmol, 1.09 equiv) was added. The resulting solution was
stirred for 2 h at 25.degree. C. The reaction was then quenched by
the addition of 10 mL of water and the reaction was extracted with
20 mL of EtOAc. The aqueous layer was adjusted to pH 4 with 6N HCl
and was extracted with 3.times.50 mL of CH.sub.2Cl.sub.2. The
combined organic layers were washed with 2.times.50 mL of brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum
to afford 75 mg (crude) of title compound as a yellow oil. MS: (ES,
m/z): 336 [M+H].sup.+.
Step-2:
(R)-1'-Benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperi-
dine]-5-carboxamide
[0435] Into a 25-mL round-bottom flask was placed
(R)-1'-benzyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxyli-
c acid (75 mg, 0.22 mmol, 1 equiv) and DMA (2 mL). This was
followed by the addition of isopropyl chloroformate (141 mg, 1.15
mmol, 5.14 equiv) dropwise with stirring at 0.degree. C. NMM (113
mg, 1.12 mmol, 5 equiv) was added dropwise with stirring at
0.degree. C. The mixture was stirred for 30 min at 0.degree. C. A
solution of NH.sub.2OH.HCl (78 mg, 1.12 mmol, 5 equiv) in DMA (1
mL) was added dropwise with stirring at 0.degree. C. The resulting
solution was stirred overnight at 25.degree. C. The solids were
filtered out and the crude product was purified by Prep-HPLC with
the following conditions: Column: XBridge Prep C18 OBD,
19.times.150 mm, 5 .mu.m; Mobile Phase A: Water/0.1% Formic acid,
Mobile Phase B: CH.sub.3CN; Gradient: 15% B up to 55% B in 7 min,
Detector: UV 254 nm, 220 nm. The collected fractions were
lyophilized to afford 25.2 mg (32% yield) of title compound as an
off-white solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. (ppm):
11.08 (s, 1H), 8.95 (s, 1H), 7.57-7.53 (m, 2H), 7.38-7.34 (m, 2H),
7.29-7.22 (m, 4H), 4.53 (s, 2H), 3.44 (d, J=16.0 Hz, 2H), 3.29-3.26
(m, 2H), 2.91 (d, J=15.6 Hz, 2H), 1.81 (d, J=17.6 Hz, 4H). MS: (ES,
m/z): 351 [M+H].sup.+.
Example 11--Preparation of
(S)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-
-carboxamide (I-35)
##STR00041##
[0436] Step-1: Methyl
(S)-1'-benzyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxyla-
te
[0437] Into a 10-mL vial was placed a solution of the second eluted
isomer from Example 9 Step 4, which was assigned as methyl
(S)-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate
as described above, (50 mg, 0.19 mmol, 1 equiv) in DMF (2 mL). This
was followed by the addition of NaH (60% in mineral oil, 8.47 mg,
0.18 mmol, 1.1 equiv) in portions at 0.degree. C. The resulting
solution was stirred for 30 min at 0.degree. C.
(Bromomethyl)benzene (35.7 mg, 0.21 mmol, 1.1 equiv) was added and
the reaction was stirred for 2 h at 25.degree. C. The reaction was
then quenched by the addition of 10 mL of ice water. The reaction
was extracted with 2.times.15 mL of EtOAc. The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and concentrated
under vacuum to afford 50 mg (74% yield) of the title compound as a
white solid. MS: (ES, m/z): 349 [M+H].sup.+.
Step-2:
(S)-1'-Benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperi-
dine]-5-carboxamide
[0438] Into a 25-mL round-bottom flask was placed methyl
(S)-1'-benzyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxyla-
te (56 mg, 0.16 mmol, 1 equiv), THF/MeOH (4:1, 3.0 mL), NH.sub.2OH
(50% in water, 516.78 mg, 10.12 mmol, 60 equiv), aq. 1N NaOH (0.3
mL, 0.26 mmol, 2 equiv). The resulting solution was stirred for 2 h
at 25.degree. C. The solids were filtered out. The crude product
was purified by Prep-HPLC with the following conditions: Column:
XBridge Prep C18 OBD, 19.times.150 mm, 5 m, Mobile Phase A:
Water/0.1% Formic acid, Mobile Phase B: CH.sub.3CN; Gradient: 5% B
up to 64% B in 7 min; Detector: UV 254 nm, 220 nm. The collected
fractions were lyophilized to afford the title compound as a white
solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. (ppm): 11.10 (s, 1H),
8.95 (s, 1H), 7.57 (s, 1H), 7.55-7.53 (d, J=8.0 Hz, 1H), 7.37-7.33
(m, 2H), 7.29-7.21 (m, 4H), 4.53 (s, 2H), 3.45-3.41 (d, J=12.0 Hz,
2H), 3.27 (s, 2H), 2.93-2.89 (d, J=15.6 Hz, 2H), 1.78 (s, 4H). MS:
(ES, m/z): 351 [M+H].sup.+.
Example 12--Preparation of
(R)--N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-piperidine]--
5-carboxamide (I-36)
##STR00042##
[0439] Step-1: Methyl
(R)-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxyla-
te
[0440] Into a 25-mL round-bottom flask was placed the first eluted
isomer from Example 9 Step 4, which was assigned as methyl
(R)-2'-oxo-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxylate
as described above, (70 mg, 0.27 mmol, 1 equiv), THF (10 mL),
Cu(OAc).sub.2 (49 mg, 0.27 mmol, 1 equiv), pyridine (32 mg, 0.40
mmol, 1.5 equiv), Et.sub.3N (82 mg, 0.81 mmol, 3 equiv) and
phenylboronic acid (165 mg, 1.35 mmol, 5 equiv). O.sub.2 (g) was
introduced to the flask and the reaction was stirred for 48 h at
60.degree. C. in an oil bath. The reaction was cooled to room
temperature, filtered and concentrated under vacuum. The residue
was purified by normal phase chromatography on silica gel using
EtOAc/petroleum ether (1:2). The collected fractions were
concentrated under vacuum to afford 40 mg (44% yield) of the title
compound as a brown oil. MS: (ES, m/z): 336 [M+H].sup.+.
Step-2:
(R)--N-Hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-piper-
idine]-5-carboxamide
[0441] Into a 25-mL round-bottom flask was placed methyl
(R)-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'-piperidine]-5-carboxyla-
te (40 mg, 0.12 mmol, 1 equiv), THF/MeOH (4:1, 2.0 mL), NH.sub.2OH
(50% in water, 946 mg, 120 equiv), aq. 1N NaOH (0.24 mL, 2 equiv).
The resulting solution was stirred for 2 h at 25.degree. C. The
solids were filtered out and the crude product was purified by
Prep-HPLC with the following conditions: Column: XBridge Prep C18
OBD, 19.times.150 mm, 5 .mu.m; Mobile Phase A: Water/0.05%
NH.sub.4OH, Mobile phase B: CH.sub.3CN; Gradient: 25% B up to 55% B
in 7 min; Detector: UV 254 nm, 220 nm. The collected fractions were
lyophilized to afford 8.0 mg (20% yield) of the title compound as a
white solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. (ppm): 11.04
(s, 1H), 8.96 (s, 1H), 7.58-7.54 (m, 2H), 7.40-7.36 (m, 2H),
7.29-7.22 (m, 4H), 3.70-3.67 (m, 2H), 3.50-3.45 (m, 2H), 3.00-2.94
(m, 2H), 1.97-1.89 (m, 4H). MS: (ES, m/z): 337 [M+H].sup.+.
TABLE-US-00007 TABLE 6 The following compound was prepared
according to the method of Example 12, with stereochemistry
assigned as described. Found (ES, m/z) Ex. Structure .sup.1H-NMR
.delta. (ppm) [M + H].sup.+ I-37 ##STR00043## (400 MHz, DMSO-d6):
11.09 (s, 1H), 8.97 (s, 1H), 7.58 (s, 1H), 7.55-7.53 (d, J = 7.6
Hz, 1H), 7.40-7.36 (m, 2H), 7.28-7.22 (m, 4H), 3.69-3.66 (m, 2H),
3.49-3.44 (m, 2H), 2.99-2.94 (m, 2H), 1.98-1.90 (m, 4H) 337
Example 13--In Vitro Histone Deacetylase Assay
[0442] The enzymatic HDAC6 assay was performed using
electrophoretic mobility shift assay. Full length human recombinant
HDAC6 protein was expressed in baculoviral system and purified by
affinity chromatography. The enzymatic reactions were assembled in
384 well plates in a total volume of 25 .mu.L in a reaction buffer
composing; 100 mM HEPES, pH 7.5, 25 mM KCl, 0.1% bovine serum
albumin, 0.01% Triton X-100, 1% DMSO (from compounds) 2 .mu.M of
the fluorescently labeled peptide substrate and enzyme. The enzyme
was added at a final concentration of 1 nM. The peptide substrate
RHKK(Ac)--NH.sub.2 was used. The compounds were tested at 12
concentrations spaced by 3.times. dilution intervals. Negative
control samples (0%-inhibition in the absence of inhibitor) and
positive control samples (100%-inhibition) were assembled in
replicates of four in each assay plate. The reactions were
incubated at 25.degree. C. and quenched by the addition of 45 .mu.L
of termination buffer (100 mM HEPES, pH 7.5, 0.01% Triton X-100,
0.05% SDS).
[0443] The terminated assay plates were analyzed on LabChip.RTM.
3000 microfluidic electrophoresis instrument (Perkin Elmer/Caliper
Life Sciences). The fluorescence intensity of the
electrophoretically separated de-acetylated product and substrate
peptide was measured. Activity in each sample was determined as the
product to sum ratio (PSR): P/(S+P), where P is the peak height of
the product peptide and S is the peak height of the substrate
peptide. Percent inhibition (Pinh) is determined using the
following equation:
[0444] Pinh=(PSR0%-PSRinh)/(PSR0%-PSR100%)*100, where PSRinh is the
product sum ratio in the presence of inhibitor, PSR0% is the
average product sum ration in the absence of inhibitor and PSR100%
is the average product sum ratio in 100%-inhibition control
samples. The IC.sub.50 values of inhibitors were determined by
fitting the %-inhibition curves with 4 parameter dose-response
model using XLfit 4 software.
[0445] As set forth in Table-7, below, IC.sub.50 values are defined
as follows: IC.sub.50.ltoreq.0.01 .mu.M (+++); IC.sub.50>0.01
.mu.M and .ltoreq.0.05 .mu.M (++) IC.sub.50>0.05 .mu.M (+).
TABLE-US-00008 TABLE-7 Inhibitory Concentration (IC.sub.50) Values
for Representative Compounds against HDAC6 HDAC6 activity IUPAC
Name Number range
(R)-N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'- (I-1)
++ pyrrolidine]-5-carboxamide
(S)-N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'- (I-2)
++ pyrrolidine]-5-carboxamide
(R)-N-hydroxy-1'-isopropyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-
(I-3) ++ pyrrolidine]-5-carboxamide
(S)-N-hydroxy-1'-isopropyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-
(I-4) + pyrrolidine]-5-carboxamide
(R)-1'-ethyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'- (I-5)
++ pyrrolidine]-5-carboxamide
(S)-1'-ethyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'- (I-6) +
pyrrolidine]-5-carboxamide
(R)-N-hydroxy-1'-isobutyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-
(I-7) ++ pyrrolidine]-5-carboxamide
(S)-N-hydroxy-1'-isobutyl-2'-oxo-1,3-dihydrospiro[indene-2,3'-
(I-8) ++ pyrrolidine]-5-carboxamide
(R)-N-hydroxy-1'-(2-methylbenzyl)-2'-oxo-1,3- (I-9) ++
dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxamide
(S)-N-hydroxy-1'-(2-methylbenzyl)-2'-oxo-1,3- (I-10) ++
dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxamide
(R)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'- (I-11)
+++ pyrrolidine]-5-carboxamide
(S)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'- (I-12)
++ pyrrolidine]-5-carboxamide
(R)-N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'- (I-13)
++ pyrrolidine]-5-carboxamide
(S)-N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'- (I-14)
++ pyrrolidine]-5-carboxamide
(R)-1'-(4-fluorophenyl)-N-hydroxy-2'-oxo-1,3- (I-15) ++
dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxamide
(S)-1'-(fluorophenyl)-N-hydroxy-2'-oxo-1,3- (I-16) ++
dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxamide
(R)-N-hydroxy-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-
(I-17) +++ 2,3'-pyrrolidine]-5-carboxamide
(S)-N-hydroxy-2'-oxo-1'-(pyridin-3-yl)-1,3-dihydrospiro[indene-
(I-18) ++ 2,3'-pyrrolidine]-5-carboxamide
(R)-N-hydroxy-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-
(I-19) ++ 2,3'-pyrrolidine]-5-carboxamide
(S)-N-hydroxy-2'-oxo-1'-(pyridin-2-yl)-1,3-dihydrospiro[indene-
(I-20) ++ 2,3'-pyrrolidine]-5-carboxamide
(R)-N-hydroxy-2'-oxo-1'-(pyridin-4-yl)-1,3-dihydrospiro[indene-
(I-21) ++ 2,3'-pyrrolidine]-5-carboxamide
(S)-N-hydroxy-2'-oxo-1'-(pyridin-4-yl)-1,3-dihydrospiro[indene-
(I-22) ++ 2,3'-pyrrolidine]-5-carboxamide
(R)-N-hydroxy-2'-oxo-1'-(pyridin-3-ylmethyl)-1,3- (I-23) ++
dihydrospiro[indene-2,3'-pyrrolidine]-5-carboxamide
(R)-N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'- (I-24) ++
pyrrolidine]-5-carboxamide
(S)-N-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'- (I-25) +
pyrrolidine]-5-carboxamide
(R)-1'-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'- (I-26) ++
pyrrolidine]-5-carboxamide
(S)-1'-benzyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'- (I-27) ++
pyrrolidine]-5-carboxamide
(R)-1'-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'- (I-28) ++
pyrrolidine]-5-carboxamide
(S)-1'-acetyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidine]-
(I-29) ++ 5-carboxamide
(R)-1'-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3 '- (I-30) +++
pyrrolidine]-5-carboxamide
(S)-1'-benzoyl-N-hydroxy-1,3-dihydrospiro[indene-2,3'- (I-31) +++
pyrrolidine]-5-carboxamide
(R)-N-hydroxy-1'-methyl-2-oxo-1,3-dihydrospiro[indene-2,3'- (I-32)
++ piperidine]-5-carboxamide
(S)-N-hydroxy-1'-methyl-2'-oxo-1,3-dihydrospiro[indene-2,3'- (I-33)
++ piperidine]-5-carboxamide
(R)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'- (I-34)
+++ piperidine]-5-carboxamide
(S)-1'-benzyl-N-hydroxy-2'-oxo-1,3-dihydrospiro[indene-2,3'- (I-35)
++ piperidine]-5-carboxamide
(R)-N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'- (I-36)
+++ piperidine]-5-carboxamide
(S)-N-hydroxy-2'-oxo-1'-phenyl-1,3-dihydrospiro[indene-2,3'- (I-37)
++ piperidine]-5-carboxamide
EQUIVALENTS
[0446] While the present invention has been described in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and other variations thereof will be
apparent to those of ordinary skill in the art. All such
alternatives, modifications and variations are intended to fall
within the spirit and scope of the present invention.
* * * * *